Therapeutic compounds and methods of use thereof

ABSTRACT

and pharmaceutically acceptable salts thereof, wherein the variables RAA, n, ring A, X1, L, m, X2, R2, R3, R4, R5, X, and R6 have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Application No. 15/896,970,filed 14 Feb. 2018, which is a continuation of International ApplicationNo. PCT/US2016/048477, filed 24 Aug. 2016, which claims the benefit ofU.S. Provisional Application No. 62/210,891, filed 27 Aug. 2015. Theentire content of the applications referenced above are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to organic compounds useful for therapy ina mammal, and in particular to inhibitors of sodium channel (e.g.,NaV1.7) that are useful for treating sodium channel-mediated diseases orconditions, such as pain, as well as other diseases and conditionsassociated with the modulation of sodium channels.

Voltage-gated sodium channels are transmembrane proteins that initiateaction potentials in nerve, muscle and other electrically excitablecells, and are a necessary component of normal sensation, emotions,thoughts and movements (Catterall, W. A., Nature (2001), Vol. 409, pp.988-990). These channels consist of a highly processed alpha subunitthat is associated with auxiliary beta subunits. The pore-forming alphasubunit is sufficient for channel function, but the kinetics and voltagedependence of channel gating are in part modified by the beta subunits(Goldin et al., Neuron (2000), Vol. 28, pp. 365-368).Electrophysiological recording, biochemical purification, and molecularcloning have identified ten different sodium channel alpha subunits andfour beta subunits (Yu, F. H., et al., Sci. STKE (2004), 253; and Yu, F.H., et al., Neurosci. (2003), 20:7577-85).

The sodium channel family of proteins has been extensively studied andshown to be involved in a number of vital body functions. Research inthis area has identified variants of the alpha subunits that result inmajor changes in channel function and activities, which can ultimatelylead to major pathophysiological conditions. The members of this familyof proteins are denoted NaV1.1 to NaV1.9.

NaV1.7 is a tetrodotoxin-sensitive voltage-gated sodium channel encodedby the gene SCN9A. Human NaV1.7 was first cloned from neuroendocrinecells (Klugbauer, N., et al., 1995 EMBO J., 14 (6): 1084-90.) and ratNaV1.7 was cloned from a pheochromocytoma PC12 cell line (Toledo-Aral,J. J., et al., Proc. Natl.Acad. Sci. USA (1997), 94:1527-1532) and fromrat dorsal root ganglia (Sangameswaran, L., et al., (1997), J. Biol.Chem., 272 (23): 14805-9). NaV1.7 is expressed primarily in theperipheral nervous system, especially nocieptors and olfactory neuronsand sympathetic neurons. The inhibition, or blocking, of NaV1.7 has beenshown to result in analgesic activity. Knockout of NaV1.7 expression ina subset of sensory neurons that are predominantly nociceptive resultsin resistance to inflammatory pain (Nassar, et al., op. cit.). Likewise,loss of function mutations in humans results in congenital indifferenceto pain (CIP), in which the individuals are resistant to bothinflammatory and neuropathic pain (Cox, J. J., et al., Nature(2006);444:894-898; Goldberg, Y. P., et al., Clin. Genet.(2007);71:311-319). Conversely, gain of function mutations in NaV1.7have been established in two human heritable pain conditions, primaryerythromelalgia and familial rectal pain, (Yang, Y., et al., J. Med.Genet. (2004), 41(3):171-4). In addition, a single nucleotidepolymorphism (R1150W) that has very subtle effects on the time- andvoltage-dependence of channel gating has large effects on painperception (Estacion, M., et al., 2009. Ann Neurol 66: 862-6; Reimann,F., et al., Proc Natl Acad Sci U S A (2010), 107: 5148-53). About 10% ofthe patients with a variety of pain conditions have the alleleconferring greater sensitivity to pain and thus might be more likely torespond to block of NaV1.7. Because NaV1.7 is expressed in both sensoryand sympathetic neurons, one might expect that enhanced pain perceptionwould be accompanied by cardiovascular abnormalities such ashypertension, but no correlation has been reported. Thus, both the CIPmutations and SNP analysis suggest that human pain responses are moresensitive to changes in NaV1.7 currents than are perturbations ofautonomic function.

Sodium channel blockers have been shown to be useful in the treatment ofpain, (see, e.g., Wood, J. N., et al., J. Neurobiol. (2004), 61(1),55-71. Genetic and functional studies have provided evidence to supportthat activity of NaV1.7 as a major contributor to pain signalling inmammals. (See Hajj, et al. Nature Reviews Neuroscience; 2013, vol 14,49-62; and Lee, et al. Cell; 2014, vol 157; 1-12). Presently, there area limited number of effective sodium channel blockers for the treatmentof pain with a minimum of adverse side effects which are currently inthe clinic. Thus there remains a need for selective voltage-gated sodiumchannel modulators (e.g., modulators of NaV1.7) that can provide agreater therapeutic index for treatment.

SUMMARY OF THE INVENTION

In one aspect the present invention provides novel compounds havingsodium channel blocking activity that are useful for the treatment ofpain. In a first embodiment (Embodiment 1; abbreviated as “E1”) theinvention provides for a compound of Formula I:

or a salt thereof; whereineach R^(AA) is independently selected from the group consisting of F,Cl, Br, I, —CN, —OR^(A1), —(X^(RA))-(6-12 membered aryl),—(X^(RA))-(5-12 membered heteroaryl), and —R^(A2), wherein said 6-12membered aryl and 5-12 membered heteroaryl of R^(AA) is optionallysubstituted with from 1 to 5 substitutents independently selectd fromthe group consisting of F, Cl, Br, I, C₁₋₁₄ alkyl, C₁₋₄ haloalkyl, andC₁₋₄(halo)alkoxy; R^(A1) is selected from the group consisting ofhydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl,phenyl and benzyl; R^(A2) is selected from the group consisting of C₁₋₈alkyl that is optionally substituted with one or more substituentsselected from oxo (=O), fluoro, amino, C₁₋₄ alkylamino anddi(C₁₋₄alkyl)amino; X^(RA) is selected from the group consisting ofabsent, —C(=O)—, and C₁₋₄ alkylene; wherein any C₁₋₄ alkylene, of X^(RA)is optionally substituted with 1 to 3 substituents selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, and phenyl that isoptionally substituted with 1 to 5 substitutents selected from, F, Cl,Br, I, —NH2, —OH, —CN, —NO_(2,) C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,C₁₋₄(halo)alkoxy, C₁₋₄ alkylamino and C₁₋₄ dialkylamino;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;ring “A” is a 3-15 membered carbocyclyl, a 6-12 membered aryl, a 5-12membered heteroaryl, or a 3-15 membered heterocyclyl;X¹ and X² are each independently selected from the group consisting ofabsent, —S—, —O— and —N(R^(x))— wherein R^(x) is H, C₁₋₈ alkyl, or C₁₋₈haloalkyl, and wherein if the subscript m is 0 then one of X¹ or X² isabsent;L is C₁₋₆ alkylene, wherein L is optionally substituted with from 1 to 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, halo, oxo (=O), and C₁₋₄ haloalkyl; wherein any twosubstituents attached to the same atom on L are optionally combined toform a 3-to 5- membered carbocyclic ring;m is 0 or 1;R², R³, R⁴, and R⁵ are each independently selected from the groupconsisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₁₋₈haloalkyl and C₁₋₈ alkoxy;X is selected from the group consisting of O, S, S=O, SO₂, N(R^(N)),C=O, CH₂, and C=S, wherein R^(N) is selected from the group consistingof H, C₁₋₆ alkyl and acyl;

ring “B” is selected from the group consisting of cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, wherein ring B isoptionally substituted with one or more groups independently selectedfrom C₁₋₄ alkyl; and

R⁶ is hydrogen or C₁₋₆ alkyl

Further embodiments of the first embodiment of compounds of theinvention are described below.

E2. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ia):

E3. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ib):

to E4. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ic):

E5. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Id):

E6. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ie):

E7. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (If):

E8. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ig):

E9. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ih):

E10. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ij):

E11. The compound of any one of E1-E10 wherein ring “B” is selected fromthe group consisting of cyclobutyl, cyclopentyl, and cyclohexyl.

E12. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ik):

E13. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Im):

E14. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (In):

E15. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Io):

E16. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ip):

to E17. The compound of claim E1 wherein the compound of formula (I) isa compound of formula (Iq):

E18. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Ir):

E19. The compound of claim E1 wherein the compound of formula (I) is acompound of formula (Is):

E20. The compound of any one of E1-E19 wherein n is 1, 2, 3, 4, 5, 6, 7,or 8.

E21. The compound of any one of E1-E19 wherein n is 2, 3, 4, 5, 6, 7, or8.

E22. The compound of any one of E1-E19 wherein wherein n is 2, 3, 4, or5.

E23. The compound of any one of E1-E22 wherein ring “A” is a 3-15membered carbocyclyl.

E24. The compound of any one of E1-E22 wherein ring “A” is a a 6-12membered aryl.

E25. The compound of any one of E1-E22 wherein ring “A” is a 6-15membered carbocycle.

E26. The compound of any one of E1-E22 wherein ring “A” is a 6-10membered aryl.

E27. The compound of any one of E1-E22 wherein ring “A” is a 3-15membered heterocycle.

E28. The compound of any one of E1-E22 wherein ring “A” is a 4-6membered heterocycle.

E29. The compound of any one of E1-E22 wherein ring “A” is selectedfrom:

E30. The compound of any one of E1-E22 wherein the group is selectedfrom the group consisting of:

E31. The compound of any one of E1-E29 wherein each R^(AA) isindependently selected from the group consisting of methyl,trifluoromethyl, ethyl, F, Cl, Br, and I.

E32. The compound of any one of E1-E31 wherein X¹is absent; X² is —O—; mis 1; and —(L)— is an optionally substituted C₁₋₄ alkylene.

E33. The compound of any one of E1-E31 wherein X¹ is absent; X² is —O—;m is 1 and —(L)— is —CH₂—, —C(H)(CH₃)—, or —CH₂—CH₂—.

E34. The compound of any one of E1-E31 wherein X¹ is absent; X² is —O—;m is 1 and —(L)— is —CH₂.

E35. The compound of any one of E1, E3,E4, E11, E12, E13, and E20-E34wherein R³ is H or F.

E36. The compound of any one of E1, E3, E4, E11, E12, E13, and E20-E35wherein R⁵ is H or Cl.

E37. The compound of any one of E1-E36 wherein R² is selected from thegroup consisting of F, Cl, Br, I, and C₃₋₈ cycloalkyl.

E38. The compound of any one of E1-E36 wherein R² is selected from thegroup consisting of Cl and cyclopropyl.

E39. The compound of any one of E1-E38 wherein R⁴ is selected from thegroup consisting of F, Cl, Br, I, and C₁₋₈ haloalkyl.

E40. The compound of any one of E1-E38 wherein R⁴ is selected from thegroup consisting of F and trifluoromentyl.

E41. The compound of any one of E1-E40 wherein R⁶ is C₁₋₆ alkyl.

E42. The compound of any one of E1-E40 wherein R⁶ is methyl.

E43. The compound of any one of E1-E40 wherein R⁶ is hydrogen.

E44. The compound of any one of E1-E43 wherein X is selected from thegroup consisting of C=O, S, S=O and SO₂.

E45. The compound of any one of E1-E43 wherein X is C=O.

E46. A compound selected from the group consisting of:

and salts thereof.

In another aspect the present invention provides for a pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect the present invention provides for a method oftreating a disease or condition in a mammal selected from the groupconsisting of pain, depression, cardiovascular diseases, respiratorydiseases, and psychiatric diseases, and combinations thereof, whereinthe method comprises administering to the mammal in need thereof atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof. In another aspect of thepresent invention said disease or condition is selected from the groupconsisting of neuropathic pain, inflammatory pain, visceral pain, cancerpain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain,childbirth pain, labor pain, neurogenic bladder, ulcerative colitis,chronic pain, persistent pain, peripherally mediated pain, centrallymediated pain, chronic headache, migraine headache, sinus headache,tension headache, phantom limb pain, dental pain, peripheral nerveinjury or a combination thereof. In another aspect of the presentinvention said disease or condition is selected from the groupconsisting of pain associated with HIV, HIV treatment inducedneuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heatsensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease,pain associated with multiple sclerosis (MS), amyotrophic lateralsclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis,rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmaldystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolardepression, anxiety, schizophrenia, sodium channel toxi relatedillnesses, familial erythromelalgia, primary erythromelalgia, familialrectal pain, cancer, epilepsy, partial and general tonic seizures,restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection underischaemic conditions cause by stroke or neural trauma, tach-arrhythmias,atrial fibrillation and ventricular fibrillation.

In another aspect the present invention provides for a method oftreating pain in a mammal by the inhibition of ion flux through avoltage-dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof.

In another aspect the present invention provides for a method ofdecreasing ion flux through a voltage-dependent sodium channel in a cellin a mammal, wherein the method comprises contacting the cell with acompound of formula I, or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a method oftreating pruritus in a mammal, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of formula I, or a pharmaceutically acceptable saltthereof.

In another aspect the present invention provides for a method oftreating cancer in a mammal, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount acompound of formula I, or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a method oftreating, but not preventing, pain in a mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof In another aspect of the present invention thepain is selected from the group consisting of neuropathic pain,inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumapain, surgical pain, post-surgical pain, childbirth pain, labor pain,neurogenic bladder, ulcerative colitis, chronic pain, persistent pain,peripherally mediated pain, centrally mediated pain, chronic headache,migraine headache, sinus headache, tension headache, phantom limb pain,dental pain, peripheral nerve injury or a combination thereof In anotheraspect the present invention the pain is associated with a disease orcondition selected from the group consisting of HIV, HIV treatmentinduced neuropathy, trigeminal neuralgia, post-herpetic neuralgia,eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome,Crohns disease, pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheralneuropathy, arthritis, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxi related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscause by stroke or neural trauma, tach-arrhythmias, atrial fibrillationand ventricular fibrillation.

In another aspect the present invention provides for a method for thetreatment or prophylaxis of pain, depression, cardiovascular disease,respiratory disease, or psychiatric disease, or a combinations thereof,in an animal which method comprises administering an effective amount ofa compound of formula I, or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a compound offormula I, or a pharmaceutically acceptable salt thereof for the use asa medicament for the treatment of diseases and disorders selected fromthe group consisting of pain, depression, cardiovascular diseases,respiratory diseases, and psychiatric diseases, or a combinationthereof.

In another aspect the present invention provides for the use of acompound of formula I, or a pharmaceutically acceptable salt thereof forthe manufacture of a medicament for the treatment of diseases anddisorders selected from the group consisting of pain, depression,cardiovascular diseases, respiratory diseases, and psychiatric diseases,or a combination thereof.

In another aspect the present invention provides for the invention asdescribed herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “alkyl”, by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain hydrocarbon radical, having the number of carbon atoms designated(i.e., C₁₋₈ means one to eight carbons). Examples of alkyl groupsinclude methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl,iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike. The term “alkenyl” refers to an unsaturated alkyl radical havingone or more double bonds. Similarly, the term “alkynyl” refers to anunsaturated alkyl radical having one or more triple bonds. Examples ofsuch unsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainhydrocarbon radical, consisting of the stated number of carbon atoms andfrom one to three heteroatoms selected from the group consisting of O,N, Si and S, and wherein the nitrogen and sulfur atoms can optionally beoxidized and the nitrogen heteroatom can optionally be quaternized. Theheteroatom(s) O, N and S can be placed at any interior position of theheteroalkyl group. The heteroatom Si can be placed at any position ofthe heteroalkyl group, including the position at which the alkyl groupis attached to the remainder of the molecule. A “heteroalkyl” cancontain up to three units of unsaturation, and also include mono- andpoly-halogenated variants, or combinations thereof. Examples include—CH₂—CH₂—O—CH_(3,) —CH₂—CH₂—O—CF_(3,) —CH₂—CH₂—NH—CH_(3,)—CH₂—CH₂—N(CH₃)-CH3, —CH₂—S—CH₂—CH_(3,) —S(O)-CH₃, —CH₂—CH₂—S(O)₂—CH₃,—CH=CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH=N—OCH₃, and —CH=CH=N(CH₃)—CH_(3.) Up totwo heteroatoms can be consecutive, such as, for example, —CH₂-—NH—OCH₃and —CH₂—O—Si(CH₃)_(3.)

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane (including branched alkane), asexemplified by —CH₂CH₂CH₂CH₂— and —CH(CH₂)CH₂CH₂—. Typically, an alkyl(or alkylene) group will have from 1 to 24 carbon atoms, with thosegroups having 10 or fewer carbon atoms being preferred in the presentinvention. “Alkenylene” and “alkynylene” refer to the unsaturated formsof “alkylene” having double or triple bonds, respectively.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH=CH—, —CH₂—CH=C(H)C H₂—O—CH₂— and—S—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like).

The terms “alkoxy,” “alkylamino” and “alkylthio”, are used in theirconventional sense, and refer to those alkyl groups attached to theremainder of the molecule via an oxygen atom (“oxy”), an amino group(“amino”) or thio group. Additionally, for dialkylamino groups, thealkyl portions can be the same or different.

The term “acyl” means a group (C₁₋₆ alkyl)—C(=O )-.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. The term “(halo)alkyl” is meant to include botha “alkyl” and “haloalkyl” substituent. Additionally, the term“haloalkyl,” is meant to include monohaloalkyl and polyhaloalkyl. Forexample, the term “C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, andthe like.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbonatoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Arylalso includes multiple condensed ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in whichat least one ring is aromatic and wherein the other rings may bearomatic or not aromatic (i.e., carbocycle). Such multiple condensedring systems are optionally substituted with one or more (e.g., 1, 2 or3) oxo groups on any carbocycle portion of the multiple condensed ringsystem. The rings of the multiple condensed ring system can be connectedto each other via fused, spiro and bridged bonds when allowed by valencyrequirements. It is to be understood that the point of attachment of amultiple condensed ring system, as defined above, can be at any positionof the ring system including an aromatic or a carbocycle portion of thering. Non-limiting examples of aryl groups include, but are not limitedto, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl,anthracenyl, and the like.

The term “carbocycle” or “carbocyclyl” refers to a single saturated(i.e., cycloalkyl) or a single partially unsaturated (e.g.,cycloalkenyl, cycloalkadienyl, etc.) all carbon ring having 3 to 7carbon atoms (i.e., (C3-C7)carbocycle). The term “carbocycle” or“carbocyclyl” also includes multiple condensed, saturated and partiallyunsaturated all carbon ring systems (e.g., ring systems comprising 2, 3or 4 carbocyclic rings). Accordingly, carbocycle includes multicycliccarbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycleshaving about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane),and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycleswith up to about 20 carbon atoms). The rings of the multiple condensedring system can be connected to each other via fused, spiro and bridgedbonds when allowed by valency requirements. For example, multicycliccarbocyles can be connected to each other via a single carbon atom toform a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), viatwo adjacent carbon atoms to form a fused connection (e.g., carbocyclessuch as decahydronaphthalene, norsabinane, norcarane) or via twonon-adjacent carbon atoms to form a bridged connection (e.g.,norbornane, bicyclo[2.2.2]octane, etc). The “carbocycle” or“carbocyclyl” can also be optionally substituted with one or more (e.g.,1, 2 or 3) oxo groups. In one embodiment the term carbocycle includes aC₃₋₁₅ carbocycle. In one embodiment the term carbocycle includes a C₆₋₁₅carbocycle. In one embodiment the term carbocycle includes a C₃₋₈carbocycle. In one embodiment the term carbocycle includes a C₃₋₆carbocycle. In one embodiment the term carbocycle includes a C₃₋₅carbocycle. Non-limiting examples of carbocycles include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,bicyclo[2.2.1]heptane, pinane, adamantane, norborene, spirocyclic C₅₋₁₂alkane, and 1-cyclohex-3-enyl.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form for example a naphthyridinyl such as1,8-naphthyridinyl), heterocycles, (to form for example a 1, 2, 3,4-tetrahydronaphthyridinyl such as1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) toform the multiple condensed ring system. Thus, a heteroaryl (a singlearomatic ring or multiple condensed ring system) has about 1-20 carbonatoms and about 1-6 heteroatoms within the heteroaryl ring. Suchmultiple condensed ring systems may be optionally substituted with oneor more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycleportions of the condensed ring. The rings of the multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is to be understood that theindividual rings of the multiple condensed ring system may be connectedin any order relative to one another. It is also to be understood thatthe point of attachment of a multiple condensed ring system (as definedabove for a heteroaryl) can be at any position of the multiple condensedring system including a heteroaryl, heterocycle, aryl or carbocycleportion of the multiple condensed ring system. It is also to beunderstood that the point of attachment for a heteroaryl or heteroarylmultiple condensed ring system can be at any suitable atom of theheteroaryl or heteroaryl multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroarylsinclude but are not limited to pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl,quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl,quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl,benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl,quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated ring that has at least oneatom other than carbon in the ring, wherein the atom is selected fromthe group consisting of oxygen, nitrogen and sulfur; the term alsoincludes multiple condensed ring systems that have at least one suchsaturated or partially unsaturated ring, which multiple condensed ringsystems are further described below. Thus, the term includes singlesaturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-memberedrings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur in thering. The ring may be substituted with one or more (e.g., 1, 2 or 3) oxogroups and the sulfur and nitrogen atoms may also be present in theiroxidized forms. Exemplary heterocycles include but are not limited toazetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle”also includes multiple condensed ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) wherein a single heterocycle ring (asdefined above) can be condensed with one or more groups selected fromheterocycles (to form for example a 1,8-decahydronapthyridinyl),carbocycles (to form for example a decahydroquinolyl) and aryls to formthe multiple condensed ring system. Thus, a heterocycle (a singlesaturated or single partially unsaturated ring or multiple condensedring system) has about 2-20 carbon atoms and 1-6 heteroatoms within theheterocycle ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the multiple condensed ring. Therings of the multiple condensed ring system can be connected to eachother via fused, spiro and bridged bonds when allowed by valencyrequirements. It is to be understood that the individual rings of themultiple condensed ring system may be connected in any order relative toone another. It is also to be understood that the point of attachment ofa multiple condensed ring system (as defined above for a heterocycle)can be at any position of the multiple condensed ring system including aheterocycle, aryl and carbocycle portion of the ring. It is also to beunderstood that the point of attachment for a heterocycle or heterocyclemultiple condensed ring system can be at any suitable atom of theheterocycle or heterocycle multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). In one embodiment theterm heterocycle includes a C₂₋₂₀ heterocycle. In one embodiment theterm heterocycle includes a C₂₋₇ heterocycle. In one embodiment the termheterocycle includes a C₂₋₅ heterocycle. In one embodiment the termheterocycle includes a C₂₋₄ heterocycle. In one embodiment the termheterocycle includes a 3-15 membered heterocycle. In one embodiment theterm heterocycle includes a 3-8 membered heterocycle. In one embodimentthe term heterocycle includes a 3-6 membered heterocycle. In oneembodiment the term heterocycle includes a 4-6 membered heterocycle.Exemplary heterocycles include, but are not limited to aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl,benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrob enzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl,spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one,2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one N-methylpiperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran,3-pyrroline, thiopyran, pyrone, tetrhydrothiophene, quinuclidine,tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane,(1s,4s)-2-azabicyclo[2.2.2]octane,(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one.

The term “heterocyclyloxy” as used herein refers to a group(heterocyclyl)—O—, wherein the term heterocyclyl has the meaning definedherein.

The term “alkoxycarbonyl” as used herein refers to a group(alkyl)—O—C(=O)—, wherein the term alkyl has the meaning defined herein.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term “chiral” refers to molecules which have theproperty of non-superimposability of the mirror image partner, while theterm “achiral” refers to molecules which are superimposable on theirmirror image partner.

As used herein, the term “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

As used herein a wavy line

that intersects a bond in a chemical structure indicates the point ofattachment of the bond that the wavy bond intersects in the chemicalstructure to the remainder of a molecule.

As used herein, the term “C-linked” means that the group that the termdescribes is attached the remainder of the molecule through a ringcarbon atom.

As used herein, the term “N-linked” means that the group that the termdescribes is attached to the remainder of the molecule through a ringnitrogen atom.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

When a bond in a compound formula herein is drawn in anon-stereochemical manner (e.g. flat), the atom to which the bond isattached includes all stereochemical possibilities. When a bond in acompound formula herein is drawn in a defined stereochemical manner(e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understoodthat the atom to which the stereochemical bond is attached is enrichedin the absolute stereoisomer depicted unless otherwise noted. In oneembodiment, the compound may be at least 51% the absolute stereoisomerdepicted. In another embodiment, the compound may be at least 80% theabsolute stereoisomer depicted. In another embodiment, the compound maybe at least 90% the absolute stereoisomer depicted. In anotherembodiment, the compound may be at least 95% the absolute stereoisomerdepicted. In another embodiment, the compound may be at least 97% theabsolute stereoisomer depicted. In another embodiment, the compound maybe at least 98% the absolute stereoisomer depicted. In anotherembodiment, the compound may be at least 99% the absolute stereoisomerdepicted.

As used herein, the term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

As used herein, the term “solvate” refers to an association or complexof one or more solvent molecules and a compound of the invention.Examples of solvents that form solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,and ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep.

As used herein, the term “pharmaceutically acceptable salts” is meant toinclude salts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrab amine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al., “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁₋₆)alkanoyloxymethyl,1-((C₁₋₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkanoyl oxy)ethyl,(C₁₋₆)alkoxycarbonyloxymethyl, N-(C₁₋₆)alkoxycarbonylaminomethyl,succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)_(2,) —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention.

The terms “treat” and “treatment” refer to both therapeutic treatmentand/or prophylactic treatment or preventative measures, wherein theobject is to prevent or slow down (lessen) an undesired physiologicalchange or disorder, such as, for example, the development or spread ofcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease or disorder, stabilized (i.e., notworsening) state of disease or disorder, delay or slowing of diseaseprogression, amelioration or palliation of the disease state ordisorder, and remission (whether partial or total), whether detectableor undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in needof treatment include those already with the disease or disorder as wellas those prone to have the disease or disorder or those in which thedisease or disorder is to be prevented.

The phrase “therapeutically effective amount” or “effective amount”means an amount of a compound of the present invention that (i) treatsor prevents the particular disease, condition, or disorder, (ii)attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, condition,or disorder described herein. For cancer therapy, efficacy can, forexample, be measured by assessing the time to disease progression (TTP)and/or determining the response rate (RR).

The term “bioavailability” refers to the systemic availability (i.e.,blood/plasma levels) of a given amount of drug administered to apatient. Bioavailability is an absolute term that indicates measurementof both the time (rate) and total amount (extent) of drug that reachesthe general circulation from an administered dosage form.

COMPOUNDS

In one aspect the present invention provides for compounds of Formula Iand its embodiments as described hereinbove.

In another embodiment, the compound is selected from compounds offormula I as described in the Examples herein and salts thereof.

SYNTHESIS OF COMPOUNDS

Compounds of formula (I) may be prepared by the process illustrated inthe schemes below.

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

In addition to one or more of the compounds provided above (orstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof), theinvention also provides for compositions and medicaments comprising acompound of formula I or and embodiment thereof and at least onepharmaceutically acceptable carrier, diluent or excipient. Thecompositions of the invention can be used to selectively inhibit NaV1.7in patients (e.g, humans).

The term “composition,” as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In one embodiment, the invention provides for pharmaceuticalcompositions (or medicaments) comprising a compound of formula I or anembodiment thereof, and its stereoisomers, geometric isomers, tautomers,solvates, metabolites, isotopes, pharmaceutically acceptable salts, orprodrugs thereof) and a pharmaceutically acceptable carrier, diluent orexcipient. In another embodiment, the invention provides for preparingcompositions (or medicaments) comprising compounds of the invention. Inanother embodiment, the invention provides for administering compoundsof formula I or its embodiments and compositions comprising compounds offormula I or an embodiment thereof to a patient (e.g., a human patient)in need thereof.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to inhibit NaV1.7 activity as required toprevent or treat the undesired disease or disorder, such as for example,pain. For example, such amount may be below the amount that is toxic tonormal cells, or the mammal as a whole.

In one example, the therapeutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.3 to 15 mg/kg/day. The daily does is, in certainembodiments, given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. In the case of a 70 kg adulthuman, the total daily dose will generally be from about 7 mg to about1,400 mg. This dosage regimen may be adjusted to provide the optimaltherapeutic response. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, intracerebral, intraocular, intralesional orsubcutaneous administration.

The compositions comprising compounds of formula I or an embodimentthereof are normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. A typicalformulation is prepared by mixing a compound of the present inventionand a diluent, carrier or excipient. Suitable diluents, carriers andexcipients are well known to those skilled in the art and are describedin detail in, e.g., Ansel, Howard C., et al., Ansel's

Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia:Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al.Remington: The Science and Practice of Pharmacy. Philadelphia:Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook ofPharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents, diluents and other known additives to provide an elegantpresentation of the drug (i.e., a compound of the present invention orpharmaceutical composition thereof) or aid in the manufacturing of thepharmaceutical product (i.e., medicament).

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water and the like. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations can also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Aactive pharmaceutical ingredient of the invention (e.g., compound offormula I or an embodiment thereof) can also be entrapped inmicrocapsules prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington: The Science and Practice of Pharmacy: Remington the Scienceand

Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philidelphia, Pa.

Sustained-release preparations of a compound of the invention (e.g.,compound of formula I or an embodiment thereof) can be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of formula I or an embodiment thereof, which matrices are inthe form of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983),non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater.Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers suchas the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate) andpoly-D-(-)-3-hydroxybutyric acid (EP 133,988A). Sustained releasecompositions also include liposomally entrapped compounds, which can beprepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci.U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A.77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).Ordinarily, the liposomes are of the small (about 200-800 Angstroms)unilamelar type in which the lipid content is greater than about 30 mol% cholesterol, the selected proportion being adjusted for the optimaltherapy.

The formulations include those suitable for the administration routesdetailed herein. The formulations can conveniently be presented in unitdosage form and can be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philidelphia, Pa. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients.

In general the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers,diluents or excipients or finely divided solid carriers, diluents orexcipients, or both, and then, if necessary, shaping the product. Atypical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. The formulations can beprepared using conventional dissolution and mixing procedures. Forexample, the bulk drug substance (i.e., compound of the presentinvention or stabilized form of the compound (e.g., complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound of the present invention is typicallyformulated into pharmaceutical dosage forms to provide an easilycontrollable dosage of the drug and to enable patient compliance withthe prescribed regimen.

In one example, compounds of formula I or an embodiment thereof may beformulated by mixing at ambient temperature at the appropriate pH, andat the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of formula I (or an embodimentthereof) is formulated in an acetate buffer, at pH 5. In anotherembodiment, the compounds of formula I or an embodiment thereof aresterile. The compound may be stored, for example, as a solid oramorphous composition, as a lyophilized formulation or as an aqueoussolution.

Formulations of a compound of the invention (e.g., compound of formula Ior an embodiment thereof) suitable for oral administration can beprepared as discrete units such as pills, capsules, cachets or tabletseach containing a predetermined amount of a compound of the invention.

Compressed tablets can be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets can bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs can be prepared for oral use. Formulationsof a compound of the invention (e.g., compound of formula I or anembodiment thereof) intended for oral use can be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients can be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets can be uncoated or can be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax can be employed.

An example of a suitable oral administration form is a tablet containingabout 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250mg, 300 mg and 500 mg of the compound of the invention compounded withabout 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose,about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving the compound, for example5-400 mg, of the invention in a suitable buffer solution, e.g. aphosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride,if desired. The solution may be filtered, e.g., using a 0.2 micronfilter, to remove impurities and contaminants.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientcan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base can include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations can desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs.

The oily phase of the emulsions of this invention can be constitutedfrom known ingredients in a known manner. While the phase can comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

In one aspect of topical applications, it is desired to administer aneffective amount of a pharmaceutical composition according to theinvention to target area, e.g., skin surfaces, mucous membranes, and thelike, which are adjacent to peripheral neurons which are to be treated.This amount will generally range from about 0.0001 mg to about 1 g of acompound of the invention per application, depending upon the area to betreated, whether the use is diagnostic, prophylactic or therapeutic, theseverity of the symptoms, and the nature of the topical vehicleemployed. A preferred topical preparation is an ointment, wherein about0.001 to about 50 mg of active ingredient is used per cc of ointmentbase. The pharmaceutical composition can be formulated as transdermalcompositions or transdermal delivery devices (“patches”). Suchcompositions include, for example, a backing, active compound reservoir,a control membrane, liner and contact adhesive. Such transdermal patchesmay be used to provide continuous pulsatile, or on demand delivery ofthe compounds of the present invention as desired.

Aqueous suspensions of a compound of the invention (e.g., compound offormula I or an embodiment thereof) contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

Formulations of a compound of the invention (e.g., compound of formula Ior an embodiment thereof) can be in the form of a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, such as a solution in1,3-butanediol or prepared as a lyophilized powder. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile fixed oilscan conventionally be employed as a solvent or suspending medium. Forthis purpose any bland fixed oil can be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid canlikewise be used in the preparation of injectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration can be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration can beprepared according to conventional methods and can be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of disorders as described below.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

When the binding target is located in the brain, certain embodiments ofthe invention provide for a compound of formula I (or an embodimentthereof) to traverse the blood-brain barrier. Certain neurodegenerativediseases are associated with an increase in permeability of theblood-brain barrier, such that a compound of formula I (or an embodimentthereof) can be readily introduced to the brain. When the blood-brainbarrier remains intact, several art-known approaches exist fortransporting molecules across it, including, but not limited to,physical methods, lipid-based methods, and receptor and channel-basedmethods.

Physical methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, circumventing the blood- brain barrier entirely, or bycreating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injectioninto the brain (see, e.g., Papanastassiou et al., Gene Therapy9:398-406, 2002), interstitial infusion/convection-enhanced delivery(see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91 :2076-2080,1994), and implanting a delivery device in the brain (see, e.g., Gill etal., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

Pharmaceutical). Methods of creating openings in the barrier include,but are not limited to, ultrasound (see, e.g., U.S. Patent PublicationNo. 2002/0038086), osmotic pressure (e.g., by administration ofhypertonic mannitol (Neuwelt, E. A., Implication of the Blood-BrainBarrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y.,1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7(see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and5,686,416).

Lipid-based methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, encapsulating the a compound of formula I (or an embodimentthereof) in liposomes that are coupled to antibody binding fragmentsthat bind to receptors on the vascular endothelium of the blood- brainbarrier (see, e.g., U.S. Patent Application Publication No.2002/0025313), and coating a compound of formula I (or an embodimentthereof) in low-density lipoprotein particles (see, e.g., U.S. PatentApplication Publication No. 2004/0204354) or apolipoprotein E (see,e.g., U.S. Patent Application Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of formulaI (or an embodiment thereof) across the blood-brain barrier include, butare not limited to, using glucocorticoid blockers to increasepermeability of the blood-brain barrier (see, e.g., U.S. PatentApplication Publication Nos. 2002/0065259, 2003/0162695, and2005/0124533); activating potassium channels (see, e.g., U.S. PatentApplication Publication No. 2005/0089473), inhibiting ABC drugtransporters (see, e.g., U.S. Patent Application Publication No.2003/0073713); coating a compound of formula I (or an embodimentthereof) with a transferrin and modulating activity of the one or moretransferrin receptors (see, e.g., U.S. Patent Application PublicationNo. 2003/0129186), and cationizing the antibodies (see, e.g., U.S. Pat.No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds can beadministered continuously by infusion into the fluid reservoirs of theCNS, although bolus injection may be acceptable. The inhibitors can beadministered into the ventricles of the brain or otherwise introducedinto the CNS or spinal fluid. Administration can be performed by use ofan indwelling catheter and a continuous administration means such as apump, or it can be administered by implantation, e.g., intracerebralimplantation of a sustained-release vehicle. More specifically, theinhibitors can be injected through chronically implanted cannulas orchronically infused with the help of osmotic minipumps. Subcutaneouspumps are available that deliver proteins through a small tubing to thecerebral ventricles. Highly sophisticated pumps can be refilled throughthe skin and their delivery rate can be set without surgicalintervention. Examples of suitable administration protocols and deliverysystems involving a subcutaneous pump device or continuousintracerebroventricular infusion through a totally implanted drugdelivery system are those used for the administration of dopamine,dopamine agonists, and cholinergic agonists to Alzheimer's diseasepatients and animal models for Parkinson's disease, as described byHarbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al.,Mov. Disord. 2: 143, 1987.

A compound of formula I (or an embodiment thereof) used in the inventionare formulated, dosed, and administered in a fashion consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. A compound of formula I (or anembodiment thereof) need not be, but is optionally formulated with oneor more agent currently used to prevent or treat the disorder inquestion. The effective amount of such other agents depends on theamount of a compound of the invention present in the formulation, thetype of disorder or treatment, and other factors discussed above.

These are generally used in the same dosages and with administrationroutes as described herein, or about from 1 to 99% of the dosagesdescribed herein, or in any dosage and by any route that isempirically/clinically determined to be appropriate.

For the prevention or treatment of disease, the appropriate dosage of acompound of formula I (or an embodiment thereof) (when used alone or incombination with other agents) will depend on the type of disease to betreated, the properties of the compound, the severity and course of thedisease, whether the compound is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the compound, and the discretion of the attendingphysician. The compound is suitably administered to the patient at onetime or over a series of treatments. Depending on the type and severityof the disease, about 1 μg/kg to 15 mg/kg (e.g., 0.1 mg/kg-10 mg/kg) ofcompound can be an initial candidate dosage for administration to thepatient, whether, for example, by one or more separate administrations,or by continuous infusion. One typical daily dosage might range fromabout 1 μg kg to 100 mg/kg or more, depending on the factors mentionedabove. For repeated administrations over several days or longer,depending on the condition, the treatment would generally be sustaineduntil a desired suppression of disease symptoms occurs. One exemplarydosage of a compound of formula I (or an embodiment thereof) would be inthe range from about 0.05 mg/kg to about 10 mg/kg. Thus, one or moredoses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or anycombination thereof) may be administered to the patient. Such doses maybe administered intermittently, e.g., every week or every three weeks(e.g., such that the patient receives from about two to about twenty,or, e.g., about six doses of the antibody). An initial higher loadingdose, followed by one or more lower doses may be administered. Anexemplary dosing regimen comprises administering an initial loading doseof about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg kgof the compound. However, other dosage regimens may be useful. Theprogress of this therapy is easily monitored by conventional techniquesand assays.

Other typical daily dosages might range from, for example, about 1 g/kgto up to 100 mg/kg or more (e.g., about 1 μg kg to 1 mg/kg, about 1μg/kg to about 5 mg/kg, about 1 mg kg to 10 mg/kg, about 5 mg/kg toabout 200 mg/kg, about 50 mg/kg to about 150 mg/mg, about 100 mg/kg toabout 500 mg/kg, about 100 mg/kg to about 400 mg/kg, and about 200 mg/kgto about 400 mg/kg), depending on the factors mentioned above.Typically, the clinician will administer a compound until a dosage isreached that results in improvement in or, optimally, elimination of,one or more symptoms of the treated disease or condition. The progressof this therapy is easily monitored by conventional assays. One or moreagent provided herein may be administered together or at different times(e.g., one agent is administered prior to the administration of a secondagent). One or more agent may be administered to a subject usingdifferent techniques (e.g., one agent may be administered orally, whilea second agent is administered via intramuscular injection orintranasally). One or more agent may be administered such that the oneor more agent has a pharmacologic effect in a subject at the same time.Alternatively, one or more agent may be administered, such that thepharmacological activity of the first administered agent is expiredprior the administration of one or more secondarily administered agents(e.g., 1, 2, 3, or 4 secondarily administered agents).

INDICATIONS AND METHODS OF TREATMENT

The compounds of the invention modulate, preferably inhibit, ion fluxthrough a voltage-dependent sodium channel in a mammal, (e.g, a human).Any such modulation, whether it be partial or complete inhibition orprevention of ion flux, is sometimes referred to herein as “blocking”and corresponding compounds as “blockers” or “inhibitors”. In general,the compounds of the invention modulate the activity of a sodium channeldownwards by inhibiting the voltage-dependent activity of the sodiumchannel, and/or reduce or prevent sodium ion flux across a cell membraneby preventing sodium channel activity such as ion flux.

Accordingly, the compounds of the invention are sodium channel blockersand are therefore useful for treating diseases and conditions inmammals, for example humans, and other organisms, including all thosediseases and conditions which are the result of aberrantvoltage-dependent sodium channel biological activity or which may beameliorated by modulation of voltage-dependent sodium channel biologicalactivity. In particular, the compounds of the invention, i.e., thecompounds of formula (I) and embodiments and (or stereoisomers,geometric isomers, tautomers, solvates, metabolites, isotopes,pharmaceutically acceptable salts, or prodrugs thereof), are useful fortreating diseases and conditions in mammals, for example humans, whichare the result of aberrant voltage-dependent NaV1.7 biological activityor which may be ameliorated by the modulation, preferably theinhibition, of NaV1.7 biological activity. In certain aspects, thecompounds of the invention selectively inhibit NaV1.7 over NaV1.5.

As defined herein, a sodium channel-mediated disease or condition refersto a disease or condition in a mammal, preferably a human, which isameliorated upon modulation of the sodium channel and includes, but isnot limited to, pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome.

In one aspect, the present invention relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of sodium channel-mediateddiseases in mammals, preferably humans and preferably diseases andconditions related to pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome, by administering to a mammal, for examplea human, in need of such treatment an effective amount of a sodiumchannel blocker modulating, especially inhibiting, agent.

A sodium channel-mediated disease or condition also includes painassociated with HIV, HIV treatment induced neuropathy, trigeminalneuralgia, glossopharyngeal neuralgia, neuropathy secondary tometastatic infiltration, adiposis dolorosa, thalamic lesions,hypertension, autoimmune disease, asthma, drug addiction (e.g., opiate,benzodiazepine, amphetamine, cocaine, alcohol, butane inhalation),Alzheimer, dementia, age-related memory impairment, Korsakoff syndrome,restenosis, urinary dysfunction, incontinence, Parkinson's disease,cerebrovascular ischemia, neurosis, gastrointestinal disease, sicklecell anemia, transplant rejection, heart failure, myocardial infarction,reperfusion injury, intermittant claudication, angina, convulsion,respiratory disorders, cerebral or myocardial ischemias, long-QTsyndrome, Catecholeminergic polymorphic ventricular tachycardia,ophthalmic diseases, spasticity, spastic paraplegia, myopathies,myasthenia gravis, paramyotonia congentia, hyperkalemic periodicparalysis, hypokalemic periodic paralysis, alopecia, anxiety disorders,psychotic disorders, mania, paranoia, seasonal affective disorder, panicdisorder, obsessive compulsive disorder (OCD), phobias, autism,Aspergers Syndrome, Retts syndrome, disintegrative disorder, attentiondeficit disorder, aggressivity, impulse control disorders, thrombosis,pre clampsia, congestive cardiac failure, cardiac arrest, Freidrich'sataxia,

Spinocerebellear ataxia, myelopathy, radiculopathy, systemic lupuserythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy,spinocerebellar ataxia, episodic ataxia, myokymia, progressive pallidalatrophy, progressive supranuclear palsy and spasticity, traumatic braininjury, cerebral oedema, hydrocephalus injury, spinal cord injury,anorexia nervosa, bulimia, Prader-Willi syndrome, obesity, opticneuritis, cataract, retinal haemorrhage, ischaemic retinopathy,retinitis pigmentosa, acute and chronic glaucoma, macular degeneration,retinal artery occlusion, Chorea, Huntington's chorea, cerebral edema,proctitis, post-herpetic neuralgia, eudynia, heat sensitivity,sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-NyhanSyndrome, Brugado syndrome, Liddle syndrome, Crohns disease, multiplesclerosis and the pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), disseminated sclerosis, diabeticneuropathy, peripheral neuropathy, charcot marie tooth syndrome,arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,myotonic dystrophy, muscular dystrophy, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, mental handicap,hypothyroidism, bipolar depression, anxiety, schizophrenia, sodiumchannel toxin related illnesses, familial erythromelalgia, primaryerythromelalgia, rectal pain, cancer, epilepsy, partial and generaltonic seizures, febrile seizures, absence seizures (petit mal),myoclonic seizures, atonic seizures, clonic seizures, Lennox Gastaut,West Syndome (infantile spasms), multiresistant seizures, seizureprophylaxis (anti-epileptogenic), familial Mediterranean fever syndrome,gout, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotectionunder ischaemic conditions caused by stroke or neural trauma,tachy-arrhythmias, atrial fibrillation and ventricular fibrillation andas a general or local anaesthetic.

As used herein, the term “pain” refers to all categories of pain and isrecognized to include, but is not limited to, neuropathic pain,inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain,orofacial pain, burn pain, burning mouth syndrome, somatic pain,visceral pain, myofacial pain, dental pain, cancer pain, chemotherapypain, trauma pain, surgical pain, post-surgical pain, childbirth pain,labor pain, chronic regional pain syndrome (CRPS),reflex sympatheticdystrophy, brachial plexus avulsion, neurogenic bladder, acute pain(e.g., musculoskeletal and post-operative pain), chronic pain,persistent pain, peripherally mediated pain, centrally mediated pain,chronic headache, migraine headache, familial hemiplegic migraine,conditions associated with cephalic pain, sinus headache, tensionheadache, phantom limb pain, peripheral nerve injury, pain followingstroke, thalamic lesions, radiculopathy, HIV pain, post-herpetic pain,non-cardiac chest pain, irritable bowel syndrome and pain associatedwith bowel disorders and dyspepsia, and combinations thereof.

Furthermore, sodium channel blockers have clinical uses in addition topain. The present invention therefore also relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of diseases or conditionssuch as cancer and pruritus (itch).

Pruritus, commonly known as itch, is a common dermatological condition.While the exact causes of pruritus are complex and incompletelyunderstood, there has long been evidence that itch involves sensoryneurons, especially C fibers, similar to those that mediate pain(Schmelz, M., et al., J. Neurosci. (1997), 17: 8003-8). In particular,it is believed that sodium influx through voltage-gated sodium channelsis essential for the propagation of itch sensation from the skin.Transmission of the itch impulses results in the unpleasant sensationthat elicits the desire or reflex to scratch.

Multiple causes and electrical pathways for eliciting itch are known. Inhumans, pruritis can be elicited by histamine or PAR-2 agonists such asmucunain that activate distinct populations of C fibers (Namer, B., etal., J. Neurophysiol. (2008),100: 2062-9). A variety of neurotrophicpeptides are known to mediate itch in animal models (Wang, H., andYosipovitch, G., International Journal of Dermatology (2010), 49: 1-11).Itch can also be elicited by opioids, evidence of distinct pharmacologyfrom that of pain responses.

There exists a complex interaction between itch and pain responses thatarises in part from the overlapping sensory input from the skin (Ikoma,A., et al., Arch. Dermatol. (2003),139: 1475-8) and also from thediverse etiology of both pain and pruritis. Pain responses canexacerbate itching by enhancing central sensitization or lead toinhibition of painful scratching. Particularly severe forms of chronicitch occur when pain responses are absent, as in the case ofpost-herpetic itch (Oaklander, A. L. , et al., Pain (2002), 96: 9-12).

The compounds of the invention can also be useful for treating pruritus.The rationale for treating itch with inhibitors of voltage-gated sodiumchannels, especially NaV1.7, is as follows:

The propagation of electrical activity in the C fibers that sensepruritinergic stimulants requires sodium entry through voltage-gatedsodium channels.

NaV1.7 is expressed in the C fibers and kerotinocytes in human skin(Zhao, P., et al., Pain (2008), 139: 90-105).

A gain of function mutation of NaV1.7 (L858F) that causeserythromelalgia also causes chronic itch (Li, Y., et al., Clinical andExperimental Dermatology (2009), 34: e313-e4).

Chronic itch can be alleviated with treatment by sodium channelblockers, such as the local anesthetic lidocaine (Oaklander, A. L., etal., Pain (2002), 96: 9-12; Villamil, A. G., et al., The AmericanJournal of Medicine (2005), 118: 1160-3). In these reports, lidocainewas effective when administered either intravenously or topically (aLidoderm patch). Lidocaine can have multiple activities at the plasmaconcentrations achieved when administered systemically, but whenadministered topically, the plasma concentrations are only about 1 μM(Center for Drug Evaluation and Research NDA 20-612). At theseconcentrations, lidocaine is selective for sodium channel block andinhibits spontaneous electrical activity in C fibers and pain responsesin animal models (Xiao, W. H., and Bennett, G. J. Pain (2008), 137:218-28). The types of itch or skin irritation, include, but are notlimited to:

psoriatic pruritus, itch due to hemodyalisis, aguagenic pruritus, anditching caused by skin disorders (e.g., contact dermatitis), systemicdisorders, neuropathy, psychogenic factors or a mixture thereof;

itch caused by allergic reactions, insect bites, hypersensitivity (e.g.,dry skin, acne, eczema, psoriasis), inflammatory conditions or injury;

itch associated with vulvar vestibulitis; and

skin irritation or inflammatory effect from administration of anothertherapeutic such as, for example, antibiotics, antivirals andantihistamines.

The compounds of the invention are also useful in treating certaincancers, such as hormone sensitive cancers, such as prostate cancer(adenocarcinoma), breast cancer, ovarian cancer, testicular cancer andthyroid neoplasia, in a mammal, preferably a human. The voltage gatedsodium channels have been demonstrated to be expressed in prostate andbreast cancer cells. Up-regulation of neonatal NaV1.5 occurs as anintegral part of the metastatic process in human breast cancer and couldserve both as a novel marker of the metastatic phenotype and atherapeutic target (Clin. Cancer Res. (2005), Aug. 1; 11(15): 5381-9).Functional expression of voltage-gated sodium channel alpha-subunits,specifically NaV1.7, is associated with strong metastatic potential inprostate cancer (CaP) in vitro. Voltage-gated sodium channelalpha-subunits immunostaining, using antibodies specific to the sodiumchannel alpha subunit was evident in prostatic tissues and markedlystronger in CaP vs non-CaP patients (Prostate Cancer Prostatic Dis.,2005; 8(3):266-73). See also Diss, J. K. J., et al., Mol. Cell.Neurosci. (2008), 37:537-547 and Kis-Toth, K., et al., The Journal ofImmunology (2011), 187:1273-1280.

In consideration of the above, in one embodiment, the present inventionprovides a method for treating a mammal for, or protecting a mammal fromdeveloping, a sodium channel-mediated disease, especially pain,comprising administering to the mammal, especially a human, in needthereof, a therapeutically effective amount of a compound of theinvention or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention wherein the compoundmodulates the activity of one or more voltage-dependent sodium channels.

In another embodiment of the invention is a method of treating a diseaseor a condition in a mammal, preferably a human, wherein the disease orcondition is selected from the group consisting of pain, depression,cardiovascular diseases, respiratory diseases, and psychiatric diseases,and combinations thereof, and wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of anembodiment of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

One embodiment of this embodiment is wherein the disease or condition isselected from the group consisting of acute pain, chronic pain,neuropathic pain, inflammatory pain, visceral pain, cancer pain,chemotherapy pain, trauma pain, surgical pain, post surgical pain,childbirth pain, labor pain, neurogenic bladder, ulcerative colitis,persistent pain, peripherally mediated pain, centrally mediated pain,chronic headache, migraine headache, sinus headache, tension headache,phantom limb pain, peripheral nerve injury, and combinations thereof.

Another embodiment of this embodiment is wherein the disease orcondition is selected from the group consisting of pain associated withHIV, HIV treatment induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritablebowel syndrome, Crohns disease, pain associated with multiple sclerosis(MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy,peripheral neuropathy, arthritic, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxin related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscaused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is a method of treating, but notpreventing, pain in a mammal, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

One embodiment of this embodiment is a method wherein the pain isselected from the group consisting of neuropathic pain, inflammatorypain, visceral pain, cancer pain, chemotherapy pain, trauma pain,surgical pain, post surgical pain, childbirth pain, labor pain, dentalpain, chronic pain, persistent pain, peripherally mediated pain,centrally mediated pain, chronic headache, migraine headache, sinusheadache, tension headache, phantom limb pain, peripheral nerve injury,trigeminal neuralgia, post herpetic neuralgia, eudynia, familialerythromelalgia, primary erythromelalgia, familial rectal pain orfibromyalgia, and combinations thereof.

Another embodiment of this embodiment is a method wherein the pain isassociated with a disease or condition selected from HIV, HIV treatmentinduced neuropathy, heat sensitivity, tosarcoidosis, irritable bowelsyndrome, Crohns disease, multiple sclerosis, amyotrophic lateralsclerosis, diabetic neuropathy, peripheral neuropathy, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia,myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses,neurogenic bladder, ulcerative colitis, cancer, epilepsy, partial andgeneral tonic seizures, restless leg syndrome, arrhythmias, ischaemicconditions caused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is the method of treating pain in amammal, preferably a human, by the inhibition of ion flux through avoltage dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of an embodiment of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, and a pharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating pruritusin a mammal, preferably a human, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of an embodiment of a compound of the invention, as set forthabove, as a stereoisomer, enantiomer or tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating cancer ina mammal, preferably a human, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of anembodiment of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of decreasing ion fluxthrough a voltage dependent sodium channel in a cell in a mammal,wherein the method comprises contacting the cell with an embodiment of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof.

Another embodiment of the invention is the method of selectivelyinhibiting a first voltage-gated sodium channel over a secondvoltage-gated sodium channel in a mammal, wherein the method comprisesadministering to the mammal an inhibitory amount of a compound offormula (I), or an embodiment of a compound of formula (I).

Another embodiment of the invention is the method of selectivelyinhibiting NaV1.7 in a mammal or a mammalian cell as compared to NaV1.5,wherein the method comprises administering to the mammal in need thereofan inhibitory amount of a compound of formula (I) or an embodiment of anembodiment thereof.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly a compound of formula I or an embodiment thereof for the useas a medicament in the treatment of such diseases and conditions.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly the use of a compound of formula I or an embodiment thereoffor the manufacture of a medicament for the treatment of such diseasesand conditions.

Another embodiment of the invention is a method of using the compoundsof formula (I) as standards or controls in in vitro or in vivo assays indetermining the efficacy of test compounds in modulatingvoltage-dependent sodium channels.

In another embodiment of the invention, the compounds of formula (I) areisotopically-labeled by having one or more atoms therein replaced by anatom having a different atomic mass or mass number. Suchisotopically-labeled (i.e., radiolabelled) compounds of formula (I) areconsidered to be within the scope of this invention. Examples ofisotopes that can be incorporated into the compounds of formula (I)include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²³I, ¹²⁵I, respectively. These isotopically-labeled compounds would beuseful to help determine or measure the effectiveness of the compounds,by characterizing, for example, the site or mode of action on the sodiumchannels, or binding affinity to pharmacologically important site ofaction on the sodium channels, particularly NaV1.7. Certainisotopically-labeled compounds of formula (I), for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

TESTING COMPOUNDS

The assessment of the compounds of the invention in mediating,especially inhibiting, the sodium channel ion flux can be determinedusing the assays described hereinbelow. Alternatively, the assessment ofthe compounds in treating conditions and diseases in humans may beestablished in industry standard animal models for demonstrating theefficacy of compounds in treating pain. Animal models of humanneuropathic pain conditions have been developed that result inreproducible sensory deficits (allodynia, hyperalgesia, and spontaneouspain) over a sustained period of time that can be evaluated by sensorytesting. By establishing the degree of mechanical, chemical, andtemperature induced allodynia and hyperalgesia present, severalphysiopathological conditions observed in humans can be modeled allowingthe evaluation of pharmacotherapies.

In rat models of peripheral nerve injury, ectopic activity in theinjured nerve corresponds to the behavioural signs of pain. In thesemodels, intravenous application of the sodium channel blocker and localanesthetic lidocaine can suppress the ectopic activity and reverse thetactile allodynia at concentrations that do not affect general behaviourand motor function (Mao, J. and Chen, L. L, Pain (2000), 87:7-17).Allometric scaling of the doses effective in these rat models,translates into doses similar to those shown to be efficacious in humans(Tanelian, D. L. and Brose, W. G., Anesthesiology (1991),74(5):949-951). Furthermore, Lidoderm®, lidocaine applied in the form ofa dermal patch, is currently an FDA approved treatment for post-herpeticneuralgia (Devers, A. and Glaler, B. S., Clin. J. Pain (2000),16(3):205-8).

The present invention readily affords many different means foridentification of sodium channel modulating agents that are useful astherapeutic agents. Identification of modulators of sodium channel canbe assessed using a variety of in vitro and in vivo assays, e.g.,measuring current, measuring membrane potential, measuring ion flux,(e.g., sodium or guanidinium), measuring sodium concentration, measuringsecond messengers and transcription levels, and using e.g.,voltage-sensitive dyes, radioactive tracers, and patch-clampelectrophysiology.

One such protocol involves the screening of chemical agents for abilityto modulate the activity of a sodium channel thereby identifying it as amodulating agent.

A typical assay described in Bean et al., J. General Physiology (1983),83:613-642, and Leuwer, M., et al., Br. J. Pharmacol (2004),141(1):47-54, uses patch-clamp techniques to study the behaviour ofchannels. Such techniques are known to those skilled in the art, and maybe developed, using current technologies, into low or medium throughputassays for evaluating compounds for their ability to modulate sodiumchannel behaviour.

Throughput of test compounds is an important consideration in the choiceof screening assay to be used. In some strategies, where hundreds ofthousands of compounds are to be tested, it is not desirable to use lowthroughput means. In other cases, however, low throughput issatisfactory to identify important differences between a limited numberof compounds. Often it will be necessary to combine assay types toidentify specific sodium channel modulating compounds.

Electrophysiological assays using patch clamp techniques is accepted asa gold standard for detailed characterization of sodium channel compoundinteractions, and as described in Bean et al., op. cit. and Leuwer, M.,et al., op. cit. There is a manual low-throughput screening (LTS) methodwhich can compare 2-10 compounds per day; a recently developed systemfor automated medium-throughput screening (MTS) at 20-50 patches (i.e.compounds) per day; and a technology from Molecular Devices Corporation(Sunnyvale, Calif.) which permits automated high-throughput screening(HTS) at 1000-3000 patches (i.e. compounds) per day.

One automated patch-clamp system utilizes planar electrode technology toaccelerate the rate of drug discovery. Planar electrodes are capable ofachieving high-resistance, cells-attached seals followed by stable,low-noise whole-cell recordings that are comparable to conventionalrecordings. A suitable instrument is the PatchXpress 7000A (AxonInstruments Inc, Union City, Calif.). A variety of cell lines andculture techniques, which include adherent cells as well as cellsgrowing spontaneously in suspension are ranked for seal success rate andstability. Immortalized cells (e.g. HEK and CHO) stably expressing highlevels of the relevant sodium ion channel can be adapted intohigh-density suspension cultures.

Other assays can be selected which allow the investigator to identifycompounds which block specific states of the channel, such as the openstate, closed state or the resting state, or which block transition fromopen to closed, closed to resting or resting to open. Those skilled inthe art are generally familiar with such assays.

Binding assays are also available. Designs include traditionalradioactive filter based binding assays or the confocal basedfluorescent system available from Evotec OAI group of companies(Hamburg, Germany), both of which are HTS.

Radioactive flux assays can also be used. In this assay, channels arestimulated to open with veratridine or aconitine and held in astabilized open state with a toxin, and channel blockers are identifiedby their ability to prevent ion influx. The assay can use radioactive22[Na] and 14[C] guanidinium ions as tracers. FlashPlate & Cytostar-Tplates in living cells avoids separation steps and are suitable for HTS.Scintillation plate technology has also advanced this method to HTSsuitability. Because of the functional aspects of the assay, theinformation content is reasonably good.

Yet another format measures the redistribution of membrane potentialusing the FLIPR system membrane potential kit (HTS) available fromMolecular Dynamics (a division of Amersham Biosciences, Piscataway,N.J.). This method is limited to slow membrane potential changes. Someproblems may result from the fluorescent background of compounds. Testcompounds may also directly influence the fluidity of the cell membraneand lead to an increase in intracellular dye concentrations. Still,because of the functional aspects of the assay, the information contentis reasonably good.

Sodium dyes can be used to measure the rate or amount of sodium ioninflux through a channel. This type of assay provides a very highinformation content regarding potential channel blockers. The assay isfunctional and would measure Na+ influx directly. CoroNa Red, SBFIand/or sodium green (Molecular Probes, Inc. Eugene Oreg.) can be used tomeasure Na influx; all are Na responsive dyes. They can be used incombination with the FLIPR instrument. The use of these dyes in a screenhas not been previously described in the literature. Calcium dyes mayalso have potential in this format.

In another assay, FRET based voltage sensors are used to measure theability of a test compound to directly block Na influx. Commerciallyavailable HTS systems include the VIPR™ II FRET system (LifeTechnologies, or Aurora Biosciences Corporation, San Diego, Calif., adivision of Vertex Pharmaceuticals, Inc.) which may be used inconjunction with FRET dyes, also available from Aurora Biosciences. Thisassay measures sub-second responses to voltage changes. There is norequirement for a modifier of channel function. The assay measuresdepolarization and hyperpolarizations, and provides ratiometric outputsfor quantification. A somewhat less expensive MTS version of this assayemploys the FLEXstation™ (Molecular Devices Corporation) in conjunctionwith FRET dyes from Aurora Biosciences. Other methods of testing thecompounds disclosed herein are also readily known and available to thoseskilled in the art.

Modulating agents so identified are then tested in a variety of in vivomodels so as to determine if they alleviate pain, especially chronicpain or other conditions such as cancer and pruritus (itch) with minimaladverse events. The assays described below in the Biological AssaysSection are useful in assessing the biological activity of the instantcompounds.

Typically, the efficacy of a compound of the invention is expressed byits IC50 value (“Inhibitory Concentration—50%”), which is the measure ofthe amount of compound required to achieve 50% inhibition of theactivity of the target sodium channel over a specific time period. Forexample, representative compounds of the present invention havedemonstrated IC50's ranging from less than 100 nanomolar to less than 10micromolar in the patch voltage clamp NaV1.7 electrophysiology assaydescribed herein.

In another aspect of the invention, the compounds of the invention canbe used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

Another aspect of the invention relates to inhibiting NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 activity,preferably NaV1.7 activity, in a biological sample or a mammal,preferably a human, which method comprises administering to the mammal,preferably a human, or contacting said biological sample with a compoundof formula (I) or a pharmaceutical composition comprising a compound offormula (I). The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, or NaV1.9 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

The compounds of the invention (or stereoisomers, geometric isomers,tautomers, solvates, metabolites, isotopes, pharmaceutically acceptablesalts, or prodrugs thereof) and/or the pharmaceutical compositionsdescribed herein which comprise a pharmaceutically acceptable excipientand one or more compounds of the invention, can be used in thepreparation of a medicament for the treatment of sodium channel-mediateddisease or condition in a mammal.

COMBINATION THERAPY

The compounds of the invention may be usefully combined with one or moreother compounds of the invention or one or more other therapeutic agentor as any combination thereof, in the treatment of sodiumchannel-mediated diseases and conditions. For example, a compound of theinvention may be administered simultaneously, sequentially or separatelyin combination with other therapeutic agents, including, but not limitedto:

opiates analgesics, e.g., morphine, heroin, cocaine, oxymorphine,levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine,propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone,meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine,butorphanol, nalbuphine and pentazocine;

non-opiate analgesics, e.g., acetomeniphen, salicylates (e.g., aspirin);

nonsteroidal antiinflammatory drugs (NSAIDs), e.g., ibuprofen, naproxen,fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac,fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin,ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam,nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetinand zomepirac;

anticonvulsants, e.g., carbamazepine, oxcarbazepine, lamotrigine,valproate, topiramate, gabapentin and pregabalin;

antidepressants such as tricyclic antidepressants, e.g., amitriptyline,clomipramine, despramine, imipramine and nortriptyline;

COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, and lumiracoxib;

alpha-adrenergics, e.g., doxazosin, tamsulosin, clonidine, guanfacine,dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1,2,3,4-tetrahydroisoquino1-2-yl)-5-(2-pyridyl) quinazoline;

barbiturate sedatives, e.g., amobarbital, aprobarbital, butabarbital,butabital, mephobarbital, metharbital, methohexital, pentobarbital,phenobartital, secobarbital, talbutal, theamylal and thiopental;

tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g., (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637), 5-[[2R,3 S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

coal-tar analgesics, in particular paracetamol;

serotonin reuptake inhibitors, e.g., paroxetine, sertraline,norfluoxetine (fluoxetine desmethyl metabolite), metabolitedemethylsertraline, '3 fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,1-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine, trazodone and fluoxetine;

noradrenaline (norepinephrine) reuptake inhibitors, e.g., maprotiline,lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine,mianserin, buproprion, buproprion metabolite hydroxybuproprion,nomifensine and viloxazine (Vivalan®)), especially a selectivenoradrenaline reuptake inhibitor such as reboxetine, in particular(S,S)-reboxetine, and venlafaxine duloxetine neurolepticssedative/anxiolytics;

dual serotonin-noradrenaline reuptake inhibitors, such as venlafaxine,venlafaxine metabolite O-desmethylvenlafaxine, clomipramine,clomipramine metabolite desmethylclomipramine, duloxetine, milnacipranand imipramine;

acetylcholinesterase inhibitors such as donepezil;

5-HT3 antagonists such as ondansetron;

metabotropic glutamate receptor (mGluR) antagonists;

local anaesthetic such as mexiletine and lidocaine;

corticosteroid such as dexamethasone;

antiarrhythimics, e.g., mexiletine and phenytoin;

muscarinic antagonists, e.g.,, tolterodine, propiverine, tropsium tchloride, darifenacin, solifenacin, temiverine and ipratropium;

cannabinoids;

vanilloid receptor agonists (e.g., resinferatoxin) or antagonists (e.g.,capsazepine);

sedatives, e.g., glutethimide, meprobamate, methaqualone, anddichloralphenazone;

anxiolytics such as benzodiazepines,

antidepressants such as mirtazapine,

topical agents (e.g., lidocaine, capsacin and resiniferotoxin);

muscle relaxants such as benzodiazepines, baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine;

anti-histamines or H1 antagonists;

NMDA receptor antagonists; 5-HT receptor agonists/antagonists;

PDEV inhibitors;

Tramadol®;

cholinergic (nicotine) analgesics;

alpha-2-delta ligands;

prostaglandin E2 subtype antagonists;

leukotriene B4 antagonists;

5-lipoxygenase inhibitors; and

5-HT3 antagonists.

Sodium channel-mediated diseases and conditions that may be treatedand/or prevented using such combinations include but not limited to,pain, central and peripherally mediated, acute, chronic, neuropathic aswell as other diseases with associated pain and other central nervousdisorders such as epilepsy, anxiety, depression and bipolar disease; orcardiovascular disorders such as arrhythmias, atrial fibrillation andventricular fibrillation; neuromuscular disorders such as restless legsyndrome and muscle paralysis or tetanus; neuroprotection againststroke, neural trauma and multiple sclerosis; and channelopathies suchas erythromyalgia and familial rectal pain syndrome.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

These examples serve to provide guidance to a skilled artisan to prepareand use the compounds, compositions and methods of the invention. Whileparticular embodiment of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinventions.

The chemical reactions in the examples described can be readily adaptedto prepare a number of other compounds of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-exemplified compounds according to the invention can be successfullyperformed by modifications apparent to those skilled in the art, forexample, by appropriately protecting interfering group, by utilizingother suitable reagents known in the art, for example, by appropriatelyprotecting interfering groups by utilizing other suitable reagents knownin the art other than those described, and/or by making routinemodifications of reaction conditions.

In the examples below, unless otherwise indicated all temperatures areset forth in degrees Celsius. Commercially available reagents werepurchased from suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge and were used without further purification unlessotherwise indicated. The reactions set forth below were done generallyunder a positive pressure of nitrogen or argon or with a drying tube(unless otherwise stated) in anhydrous solvents, and the reaction flaskswere typically fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. ¹H NMR spectra were obtained in deuterated CDCl₃, d₆-DMSO,CH₃OD or d₆-acetone solvent solutions (reported in ppm) using ortrimethylsilane (TMS) or residual non-deuterated solvent peaks as thereference standard. When peak multiplicities are reported, the followingabbreviates are used: s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet, br (broadened), dd (doublet of doublets), dt(doublet of triplets). Coupling constants, when given, ar reported in Hz(Hertz).

All abbreviations used to describe reagents, reaction conditions orequipment are intended to be consistent with the definitions set forthin the following list of Abbreviations. The chemical names of discretecompounds of the invention were typically obtained using the structurenaming feature of ChemDraw naming program.

ABBREVIATIONS

-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   HPLC High Pressure Liquid Chromatography-   LCMS Liquid Chromatography Mass Spectrometry-   RT Retention time

EXAMPLES

Examples 1 and 2 Synthesis of(1R,2R)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-l-carboxylicacid and (1S,2S)-2-(4- adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-l-carboxylic acid

Step 1. Preparation of4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl chloride

To a cooled (0° C.) suspension of4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (Preparedas described in International Patent Application Publication NumberWO2013177224; 0.75 g, 2.18 mmol) in dichloromethane (12 mL) was addedoxalyl chloride (0.95 mL, 10.9 mmol) followed by dimethyl formamide (2drops, catalytic). The suspension was warmed to ambient temperature andstirred for 5 hours, resulting in a pale yellow solution. The reactionsolvent was concentrated in vacuo and the resulting solid (0.59 g, 74%yield) was used in step 2 without further purification.

Step 2. Preparation of ethyl 2-iodocyclopentane-l-carboxylate

To a stirred solution of polymer bound triphenylphosphine (3.0 mmol/g,1.45 g, 4.3 mmol), iodine (1.27 g, 5.0 mmol), and imidazole (0.34 g, 5.0mmol) in dichloromethane (20 mL) was added a solution of ethyl2-hydroxycyclopentane-l-carboxylate (1.15 g, 7.3 mmol) indichloromethane (13 mL). The reaction mixture was stirred at 30° C. for65 hours, diluted with dichloromethane (50 mL), filtered through celiteand concentrated in vacuo. The residue was purified by flashchromatography eluting with ethyl acetate in hexanes to afford the titlecompound as a colorless liquid (0.62 g, 69% yield): ¹H NMR (300 MHz,CDCl₃) δ 4.38-4.31 (m, 1H), 4.22-4.12 (m, 2H), 3.13-3.06 (m, 1H),2.60-2.46 (m, 1H), 2.36-2.25 (m, 1H), 2.14-2.02 (m, 2H), 1.86-1.71 (m,2H), 1.31-1.25 (m, 3H).

Step 3. Preparation of ethyl(1,2-trans)-2-(4-adamantan-l-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-l-carboxylate

A 25 mL round bottom flask was charged with ethyl2-iodocyclopentane-l-carboxylate (0.13 g, 0.48 mmol),4,7-diphenyl-1,10-phenanthroline (0.024 g, 0.072 mmol), anhydrousmagnesium chloride (0.069 g, 0.72 mmol), nickel(II) acetylacetonate(0.013 g, 0.048 mmol) and acid-washed zinc dust (0.095 g, 1.45 mmol).The flask was evacuated and flushed with argon gas twice to removeoxygen. A suspension of4-adamantan-l-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl chloride (0.35g, 0.97 mmol) in degassed acetonitrile (3 mL) was added dropwise viasyringe. The resulting red-brown suspension was stirred for 16 hoursunder an argon atmosphere. The reaction mixture was diluted withacetonitrile and filtered to remove the solids. The filtrate wasconcentrated and the residue was diluted with ethyl acetate (30 mL) andwater (15 mL). The aqueous layer was isolated and extracted with ethylacetate (3×25 mL). The combined organic layers were washed with brine;dried over anhydrous magnesium sulfate, filtered and concentrated invacuo. The residue was purified by flash chromatography eluting withethyl acetate in hexanes to afford the title compound as a colorlesssolid (0.099 g, 44% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.44 (d, J=8.5 Hz,1H), 6.50 (d, J=13.4 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.97-3.90 (m, 1H),3.54 (s, 2H), 3.46-3.38 (m, 1H), 2.28-1.98 (m, 6H), 1.97-1.54 (m, 16H),1.19 (t, J=7.1 Hz, 3H), 0.93-0.87 (m, 2H), 0.67-0.62 (m, 2H); MS (ES+)m/z 491.3 (M+1).

Step 4. Synthesis of(1,2-trans)-2-(4-adamantan-l-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylicacid

To a solution of ethyl(1R,2R)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylate(0.099 g, 0.21 mmol) in tetrahydrofuran (4 mL) was added aqueoussolution of lithium hydroxide (0.2 M, 0.63 mmol, 3.14 mL). The reactionmixture was stirred at ambient temperature for 16 h. The reaction waspartially concentrated and diluted with diethyl ether (50 mL). Thelayers were separated and the aqueous layer was extracted with diethylether (2×20 mL). The aqueous layer was acidified with 1M aqueoushydrochloric acid, and extracted with ethyl acetate (3×25 mL). Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by reverse-phase LC to afford racemic(1,2-trans)-2-(4-adamantan-l-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylic acid (0.033 g, 36%). The racemic material was purified bySFC to afford the pure enantiomer((1R,2R)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-l-carboxylicacid and(1S,2S)-2-(4-adamantan-l-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-l-carboxylicacid)) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.45 (d, J=8.5Hz, 1H), 6.50 (d, J=13.5 Hz, 1H), 3.98-3.87 (m, 1H), 3.57-3.46 (m, 1H),3.54 (s, 2H), 2.29-1.87 (m, 8H), 1.86-1.61 (m, 14H), 0.97-0.86 (m, 2H),0.71-0.61 (m, 2H); MS (ES+) m/z 442.2, 441.2 (M+1), (ES−) m/z 440.2,439.2 (M−1).

Examples 3 and 4 Synthesis of(1,2-cis)-2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclopentane-1-carboxylicacid and(1,2-trans)-2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclopentane-1-carboxylic

To a cooled (−78 ° C.) solution of1-((4-bromo-2-chloro-5-fluorophenoxy)methyl) adamantane (1.50 g, 4.01mmol) in tetrahydrofuran (9 mL) was added a solution of butyllithium(1.6 M, 4.42 mmol, 2.8 mL). The solution was stirred at −78° C. for 0.5h before a pre-cooled (−78° C.) solution oftetrahydro-1H-cyclopent[c]furan-1,3(3aH)-dione (0.68 g, 4.81 mmol) intetrahydrofuran (12 mL) was added dropwise via cannula. The reaction waswarmed to ambient temperature and stirred for 16 h. The reaction wasre-cooled (−78° C.) then quenched with saturated aqueous ammoniumchloride (10 mL) and warmed to ambient temperature. The aqueous layerwas isolated and extracted with ethyl acetate (3×50 mL). The combinedorganics were dried over anhydrous sodium sulfate, decanted andconcentrated in vacuo. The resulting residue was purified by flashchromatography eluting with ethyl acetate in hexanes to afford2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclopentane-l-carboxylicacid (cis/trans mixture) contaminated withtetrahydro-1H-cyclopent[c]furan-1,3(3aH)-dione (0.55 g). A portion ofcrude material (0.20 g) was further purified by reverse-phase LC toafford(1,2-cis)-2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclopentane-1-carboxylicacid (0.011 g); ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=7.6 Hz, 1H), 6.60(d, J=12.7 Hz, 1H), 4.03-3.89 (m, 1H), 3.57 (s, 2H), 3.11-2.98 (m, 1H),2.24-1.88 (m, 7H), 1.85-1.61 (m, 14H); MS (ES+) m/z 417.1, 435.1, 437.1,(ES−) m/z 413.2, 433.2, 435.2.(1,2-trans)-2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclopentane-1-carboxylic acid was also obtained as a colorless solid (0.014 g): ¹HNMR (300 MHz, CDCl₃) δ 7.92 (d, J=7.7 Hz, 1H), 6.62 (d, J=12.8 Hz, 1H),4.00-3.87 (m, 1H), 3.57 (s, 2H), 3.57-3.47 (m, 1H), 2.29-1.87 (m, 7H),1.87-1.60 (m, 14H); MS (ES+) m/z 417.1, 435.1, 437.1, (ES−) m/z 413.2,433.2, 435.2.

Example 5 Synthesis of(1,2-trans)-2-(4-adamantan-l-yl)methoxy)-5-cyclopropyl-2-fluorobenzyl)cyclopentane-l-carboxylicacid

Step 1. Preparation of methyl2-(4-adamantan-l-yl)methoxy)-5-chloro-2-fluorobenzoyl)-cyclopentane-1-carboxylate(cis/trans mixture)

To a solution of crude2-(4-adamantan-l-yl)methoxy)-5-chloro-2-fluorobenzoyl)-cyclopentane-1-carboxylicacid (cis/trans mixture) (0.35 g) in toluene (4 mL) and methanol (1 mL)was added a solution of trimethylsilyldiazomethane in hexanes (2.0 M,1.0 mL, 2.01 mmol). The reaction solution was stirred for 20 minutesthen trimethylsilyldiazomethane solution (0.5 mL, 1.0 mmol) was added.The reaction was stirred for an additional 0.5 h, then cooled andquenched with glacial acetic acid (0.5 mL).s. The filtrate wasconcentrated and the residue was purified by column chromatographyeluting with ethyl acetate in hexanes to afford methyl(1R,2S)-2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclopentane-1-carboxylate (cis/trans mixture) (0.095 g, 26%yield): 1,2-cis: ¹H NMR (300 MHz, CdCl₃) δ 7.87 (d, J=7.7 Hz, 1H), 6.61(d, J=12.7 Hz, 1H), 3.98-3.87 (m, 1H), 3.64 (s, 3H), 3.56 (s, 2H),3.11-3.01 (m, 1H), 2.19-1.61 (m, 21H); Also obtained 1,2-trans: ¹H NMR(300 MHz, CdCl₃) δ 7.92 (d, J=7.7 Hz, 1H), 6.62 (d, J=12.7 Hz, 1H), 3.92(dd, J=7.5, 15.1 Hz, 1H), 3.65 (s, 3H), 3.57 (s, 2H), 3.47 (dd, J=8.7,15.3 Hz, 1H), 2.28-1.97 (m, 6H), 1.95-1.61 (m, 15H); MS (ES +) m/z 491.3(M +1).

Step 2. Synthesis of methyl(trans)-2-(4-adamantan-l-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-l-carboxylate

A mixture of methyl(1R,2S)-2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)-cyclopentane-1-carboxylate(cis/trans mixture) (0.095 g, 0.212 mmol), cyclopropylboronic acid (27.3mg, 0.318 mmol) and potassium phosphate (0.202 g, 0.954 mmol) in toluene(4 mL) and water (0.4 mL) was sparged with argon gas for 15 min beforetricyclohexylphosphine tetrafluoroborate (16 mg, 0.092 mmol) andpalladium acetate (5 mg, 0.021 mmol) were added. The reaction mixturewas heated to 110° C. for 18 h and then cooled to ambient temperature.The solids were removed by filtration and rinsed with water (25 mL) andethyl acetate (50 mL). The aqueous layer was isolated and extracted withethyl acetate (3×25 mL). The combined organic layers were washed withbrine; dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography eluting withethyl acetate in hexanes to afford the title compound (0.074 g, 77%yield): ¹H NMR (300 MHz, CdCl₃) δ 7.45 (d, J=8.5 Hz, 1H), 6.50 (d,J=13.5 Hz, 1H), 3.94 (dd, J=7.0, 14.7 Hz, 1H), 3.64 (s, 3H), 3.54 (s,2H), 3.47 (dd, J=7.1, 15.3 Hz, 1H), 2.25-1.98 (m, 6H), 1.93-1.61 (m,16H), 0.94-0.88 (m, 2H), 0.68-0.61 (m, 2H); MS (ES+) m/z 491.3 (M+1).

Step 3. Synthesis of methyl(1,2-trans)-24(R/S)-(4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorophenyl)(hydroxy)methyl)cyclopentane-1-carboxylate

To a cooled (0° C.) suspension of methyl(1,2-trans)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylate(0.074 g, 0.163 mmol) in anhydrous methanol (3 mL) was added sodiumborohydride (0.005 g, 0.132 mmol). The reaction mixture was warmed toambient temperature and stirred for 16 h. The reaction was concentratedand diluted with diethyl ether (50 mL) and water (20 mL). The layerswere separated and the aqueous layer was extracted with diethyl ether(3×30 mL). The combined organic layers were washed with brine, driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by flash chromatography eluting with ethylacetate in hexanes to afford the title compound (0.07 g, 94% yield). Thecrude residue was subj ected into step 4 without any furthercharacterization.

Step 4. Synthesis of methyl(1,2-trans)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzyl)cyclopentane-1-carboxylate

To a cooled (0° C.) solution of methyl(1,2-trans)-2-((R/S)-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorophenyl)(hydroxy)methyl)cyclopentane-1-carboxylate(0.070 g, 0.15 mmol) in dichloromethane (1.5 mL) was addedtriethylsilane (0.050 mL, 0.31 mmol) followed by boron trifluoridediethyl etherate (0.040 mL, 0.31 mmol). The yellow solution was slowlywarmed (over 1 h) to ambient temperature and stirred for an additional 3h. The reaction was cooled (0° C.) and carefully quenched with saturatedaqueous sodium bicarbonate solution (10 mL). The layers were separatedand the aqueous layer was extracted with dichloromethane (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by flash chromatography with a gradient 0% to 50%dichloromethane in hexanes to afford the title compound (0.063 g, 93%).The crude residue was subj ected into step 5 without any furthercharacterization.

Step 5. Synthesis of(1,2-trans)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzyl)cyclopentane-1-carboxylicacid

Following the procedure as described in Example 1 (Step 4) and makingnon-critical variations as required to replace ethyl(1R,2R)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylatewith methyl(1,2-trans)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzyl)cyclopentane-1-carboxylate,the title compound was obtained following purification by reverse-phaseas a colorless solid (0.0145 g, 24% yield): ¹H NMR (300 MHz, CdCl₃) δ6.64 (d, J=8.6 Hz, 1H), 6.48 (d, J=11.8 Hz, 1H), 3.45 (s, 2H), 2.76 (dd,J=4.2, 13.4 Hz, 1H), 2.59-2.35 (m, 3H), 2.11-1.83 (m, 6H), 1.83-1.58 (m,15H), 1.37-1.21 (m, 1H), 0.96-0.81 (m, 2H), 0.66-0.53 (m, 2H); MS (ES+)m/z 427.2, 428.2, (ES -) m/z 425.3, 426.3.

Example 6 Synthesis oftrans-2-(44-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclohexane-1-carboxylicacid

Step 1. Preparation of2-(4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoyl)-cyclohexanecarboxylicacid

To a cooled (0° C.) stirred solution of1-((4-bromo-2-chloro-5-fluorophenoxy)methyl)adamantane (0.5 g, 1.34mmol) in tetrahydrofuran (8 mL) was added a solution ofisopropylmagnesium chloride lithium chloride complex in tetrahydrofuran(1.3 M, 2.2 mL, 2.81 mmol) dropwise. The reaction mixture was stirred at0° C. for 1 h, and further solution of isopropylmagnesium chloridelithium chloride complex in tetrahydrofuran (1.3 M, 0.52 mL, 0.67 mmol)was added dropwise. The reaction mixture was stirred at 0° C. for 1 h,cis-1,2-cyclohexanedicarboxylic anhydride (0.31 g, 2.00 mmol) was addedin one portion and stirring was continued at 0° C. for another 1 h. Anaqueous solution of saturated ammonium chloride (20 mL) was added andthe mixture was extracted with ethyl acetate (3×30 mL). The combinedorganic layers were washed with brine (30 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue wastriturated with hexanes to afford the title compound as a colorlesssolid (0.28 g, 70% yield): ¹H NMR (300 MHz, CDCl₃) δ7.87-7.76 (m, 1H),6.66-6.55 (m, 1H), 3.72-3.62 (m, 1H), 3.56 (s, 2H), 2.79-2.69 (m, 1H),2.19-1.91 (m, 5H), 1.87-1.64 (m, 4H), 1.51-1.26 (m, 4H); MS (ES+) m/z949.2, 951.2 (M+1).

Step 2. Preparation of methyl2-(4-((adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclohexane-1-carboxylate

To a cooled (0° C.) stirred solution of2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoyl)cyclohexanecarboxylicacid (0.27 g, 0.6 mmol) was added a solution of(trimethylsilyl)diazomethane in hexanes (0.3 mL, 2M solution in hexanes,1.2 mmol) dropwise. The reaction mixture was stirred at ambienttemperature for 2 h and concentrated in vacuo. The residue was purifiedby column chromatography eluting with ethyl acetate in hexanes to affordthe title compound as colorless oil (0.18 g, 65% yield): MS (ES+) m/z465.2, 463.2 (M +1).

Step 3. Preparation of methyl2-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclohexane-1-carboxylate

Following the procedure as described in Example 5 (Step 2) and makingnon-critical variations as required to replace methyl(1R,2S)-2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclopentane-1-carboxylate(cis/trans mixture) with methyl2-(4-((adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclohexane-1-carboxylate,the title compound was obtained as a colorless solid (0.14 g, 77% yield)which was used in step 4 without any further characterization: MS (ES+)m/z 491.3 (M+1);

Step 4. Synthesis oftrans-2-(4-((-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclohexane-1-carboxylicacid

Following the procedure as described in Example 1 (Step 4) and makingnon-critical variations as required to replace ethyl(1R,2R)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylatewith methyl2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclohexane-1-carboxylate,title compound was obtained following re-crystallized from methanol toafford the title compound as a colorless solid (0.057 g, 45%): ¹H NMR(300 MHz, CdCl₃) δ 7.48-7.42 (m, 1H), 6.53-6.44 (m, 1H), 3.54 (s, 2H),3.45-3.33 (m, 1H), 2.92-2.78 (m, 1H), 2.23-1.95 (m, 6H), 1.90-1.61 (m,14H), 1.54-1.24 (m, 3H), 1.20-1.03 (m, 1H), 0.94-0.82 (m, 2H), 0.71-0.58(m, 2H); MS (ES+) m/z 455.1 (M+1).

Example 7 Synthesis oftrans-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclobutane-1-carboxylicacid (racemic mixture

Step 1. Preparation of2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclobutane-1-carboxylicacid

To a cooled (−78° C.) stirred solution of1-((4-bromo-2-chloro-5-fluorophenoxy)-methyl)adamantane (0.5 g, 1.34mmol) in tetrahydrofuran (3 mL) was added a solution of n- butyl lithium(0.9 mL, 1.6 M solution in tetrahydrofuran, 1.47 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 0.5 h and was added via acannula to a cooled (−78° C.) stirred solution of3-oxabicyclo[3.2.0]heptane-2,4-dione (0.2 g, 1.61 mmol) intetrahydrofuran (4 mL). Stirring was continued at −78° C. for 4 h. Anaqueous solution of saturated ammonium chloride (20 mL) and water (20mL) were added, and the mixture was extracted with ethyl acetate (3×30mL). The combined organic layers were washed with water (30 mL) andbrine (30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyusing gradient 0% to 20% ethyl acetate with 0.2% formic acid in hexanesto afford the title compound as yellow solid (0.085 g, 23% yield): MS(ES+) m/z 420.8, 418.8 (M−1).

Step 2. Preparation of methyl2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclobutane-1-carboxylate

To a stirred solution of 2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)-cyclobutane-1-carboxylic acid (0.062 g, 0.15 mmol) was added asolution of (trimethylsilyl)-diazomethane in hexanes (2.0 M, 0.29 mmol,0.2 mL) dropwise. The reaction mixture was stirred at ambienttemperature for 4 h, (trimethylsilyl)diazomethane in hexanes (2.0 M,0.15 mmol, 0.1 mL) was added dropwise, and stirring was continued atambient temperature for 0.5 h. The solvent was concentrated in vacuo toafford the title compound as a yellow solid (0.059 g, 92% yield): MS(ES+) m/z 437.0, 435.1 (M+1).

Step 3. Preparation of methyl2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclobutane-1-carboxylate

A mixture of methyl2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)-cyclobutane-1-carboxylate(0.08 g, 0.18 mmol), cyclopropylboronic acid (0.05 g, 0.55 mmol) andpotassium phosphate (0.18 g, 0.83 mmol) in toluene (2.3 mL) and water(0.1 mL) was purged with argon for 10 min, and tricyclohexylphosphinetetrafluoroborate (0.014 g, 0.04 mmol) and palladium acetate (0.004 g,0.02 mmol) were added. The reaction mixture was heated to 130° C. for0.5 h in the microwave and then cooled to ambient temperature.Hydrochloric acid (1 M, 20 mL) was added and the mixture was extractedwith ethyl acetate (3×40 mL). The combined organic layers were washedwith brine; dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyeluting with ethyl acetate in hexanes to afford the title compound as ayellow oil (0.08 g, 43% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.47 (d, J=8.4Hz, 1H), 6.48 (d, J=13.3 Hz, 1H), 3.68 (s, 3H), 3.54 (s, 2H), 2.42-2.00(m, 7H), 1.80-1.62 (m, 15H), 0.94-0.88 (m, 2H), 0.68-0.61 (m, 2H).

Step 4. Synthesis oftrans-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclobutane-1-carboxylicacid

Following the procedure as described in Example 1 (Step 4) and makingnon-critical variations as required to replace ethyl(1R,2R)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylatewith methyl 2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclobutane-1-carboxylate, title compoundwas obtained following purification by column chromatography usinggradient 0% to 20% ethyl acetate with 0.2% formic acid in hexanes as acolorless solid (0.019 g, 25% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 12.29(br s, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.90 (d, J=13.5 Hz, 1H), 4.00 (q,J=8.7 Hz, 1H), 3.66 (s, 2H), 3.41-3.24 (m, 2H), 2.31-1.91 (m, 6H),1.75-1.57 (m, 13H), 0.93-0.90 (m, 2H), 0.64-0.62 (m, 2H); MS (ES+) m/z427.1 (M+1).

Example 8 Synthesis oftrans-2-(4-(benzyloxy)-5-cyclopropyl-2-fluorobenzoyl)-cyclopentane-1-carboxylicacid

s Step 1. Preparation of diethyl trans cyclopentane-1,2-dicarboxylate

To a solution of trans cyclopentane-1,2-dicarboxylic acid (5.00 g, 31.62mmol) in absolute ethanol (100 mL) was added concentrated sulfuric acid(3 mL). The reaction mixture was fitted with a condenser and heated atreflux for 16 h, after which it was evaporated dry in vacuo. Theresulting residue was diluted with saturated sodium bicarbonate (100mL), and washed with dichloromethane (3×100 mL). The combined organicextracts were dried over anhydrous magnesium sulfate and concentrated invacuo to afford the title compound as light yellow oil (6.10 g, 90%yield), which was used directly for the next step.

Step 2. Preparation of trans-2-(ethoxycarbonyl)cyclopentane-1-carboxylicacid

To a solution of diethyl trans-cyclopentane-1,2-dicarboxylate (6.09 g,28.46 mmol) in ethanol (28.0 mL) was added a solution of potassiumhydroxide (2.07 g, 37.00 mmol) in water and ethanol (20.2 mL, 1:5). Thereaction mixture was stirred at room temperature overnight, after whichit was diluted with hydrochloric acid (1 mol/L in water) and washed withethyl acetate (3×100 mL). The combined organic extracts were dried overanhydrous magnesium sulfate, filtered, and concentrated. The resultingsyrup was purified by column chromatography eluting with ethyl acetateto afford the title compound as a pale yellow oil (2.76 g, 52% yield):¹H NMR (300 MHz, CDCl₃) δ 4.93 (q, J=6.9 Hz, 2H), 3.18-3.03 (m, 2H),2.11-2.02 (m, 2H), 1.89-1.69 (m, 4H), 1.23 (t, J=7.2 Hz, 3H).

Step 3. Preparation of ethyl trans2-(chlorocarbonyl)cyclopentane-1-carboxylate

To a solution of trans 2-(ethoxycarbonyl)cyclopentane-1-carboxylic acid(2.76 g, 14.85 mmol) in anhydrous dichloromethane (30 mL) was slowlyadded thionyl chloride (15 mL). The reaction mixture was stirred at roomtemperature overnight, after which TLC analysis indicated completeconsumption of the starting material. The solvent was removed in vacuoto afford the title compound which was used in step 4 without furtherpurification.

Step 4. Preparation of ethyl trans2-(4-(benzyloxy)-5-chloro-2-fluorobenzoyl)-cyclopentane-1-carboxylate

To a cooled (−50° C.), stirred solution of1-(benzyloxy)-4-bromo-2-chloro-5-fluorobenzene (2.35 g, 7.42 mmol) intetrahydrofuran (15.0 mL) was added a solution of isopropylmagnesiumchloride lithium chloride complex (1.3 mol/L in THF, 1.5 equivalents)dropwise over 5 minutes. After 20 minutes, the reaction mixture wascooled to −78° C., and a solution of ethyl trans2-(chlorocarbonyl)cyclopentane-1-carboxylate (14.9 mmol) dissolved intetrahydrofuran (20 mL) was added dropwise. The reaction mixture wasstirred at the same temperature for 3 h then quenched with saturatedammonium chloride (75 mL), washed with ethyl acetate (3×75 mL), and thecombined organic extracts were dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography eluting with ethyl acetate in hexanes to afford the titlecompound as a clear oil (2.11 g, 70% yield): ¹H NMR (300 MHz, CDCl₃) δ7.92 (d, J=7.5 Hz, 1H), 7.47-7.25 (m, 5H), 6.69 (d, J=12.3 Hz, 1H), 5.15(s, 2H), 4.07 (q, J=7.2 Hz, 2H), 3.92-3.85 (m, 1H), 3.40 (q, J=7.8 Hz,1H), 2.16-2.02 (m, 2H), 1.93-1.57 (m, 4H), 1.67 (t, J=6.9 Hz, 3H); MS(ES+) m/z 407.2, 405.1 (M+1).

Step 5. Preparation of ethyl trans2-(4-(benzyloxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylate

Following the procedure as described in Example 5 (Step 2) and makingnon-critical variations as required to replace methyl2-(4-adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoyl)cyclopentane-1-carboxylate(cis/trans mixture) with ethyl trans 2-(4-(b enzyloxy)-5-chloro-2-fluorobenzoyl)cyclopentane- 1-carboxyl ate, the title compoundwas obtained as a yellow oil (0.15 g, 10% yield): ¹H NMR (300 MHz,CDCl₃) δ 7.51-7.20 (m, 6H), 6.67-6.50 (m, 1H), 5.20-5.05 (m, 2H),4.17-4.05 (m, 2H), 3.97-3.80 (m, 1H), 3.50-3.32 (m, 1H), 2.25-1.95 (m,3H), 1.95-1.55 (m, 4H), 1.27-1.05 (m, 3H), 0.91 (br s, 2H), 0.67 (br s,2H), MS (ES+) m/z 411.1 (M+1).

Step 6. Preparation of trans2-(4-(benzyloxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylicacid

Following the procedure as described in Example 1 (Step 4) and makingnon-critical variations as required to replace ethyl2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylatewith ethyl trans2-(4-(benzyloxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylate,the title compound was obtained following lyophilization fromacetonitrile (0.5 mL) and water (5.0 mL) as a pale yellow solid: ¹H NMR(300 MHz, DMSO-d₆) δ 7.45-7.33 (m, 6H), 6.59 (d, J=12.4 Hz, 1H), 3.92(q, J=6.9 Hz, 1H), 3.98 (q, J=7.8 Hz, 1H), 2.21-1.66 (m, 7H), 0.93-0.88(m, 2H), 0.69-0.64 (m, 2H); MS (ES−) m/z 381.1 (M−1).

Example 9 Synthesis of (1,2-trans)-2-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)cyclopentane-1-carboxylicacid

Step 1. Preparation of(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoylchloride

To a cooled (0° C.) suspension(S)-5-cyclopropyl-4-(1-(1-(3,5-dichlorophenyl)ethyl)-piperidin-4-yl)methoxy)-2-fluorobenzoicacid (Prepared accordingly as described in International PatentApplication Publication Number WO2013177224) (0.60 g, 1.29 mmol) indichloromethane (15 mL) was added oxalyl chloride (0.56 mL, 6.43 mmol)followed by dimethyl formamide (2 drops, catalytic). The suspension waswarmed to ambient temperature and stirred for 4 h, resulting in a paleyellow solution. The reaction was concentrated and the resulting crudesolid (0.65 g, quantitative yield) was used without furtherpurification.

Step 2. Synthesis of ethyl(1,2-trans)-2-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-piperidin-4-yl)methoxy)-2-fluorobenzoyl)cyclopentane-1-carboxylate

Following the procedure as described in Example 1 (Step 3) and makingnon-critical variations as required to replace4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl chloride with(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoylchloride, the title compound was obtained as a colorless gum (0.20 g,51% yield). The residue was used in step 3 without any furtherpurification: MS (ES+) m/z 592.3, 590.3 (M+1).

Step 3. Synthesis of(1,2-trans)-2-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-piperidin-4-yl)methoxy)-2-fluorobenzoyl)cyclopentane-1-carboxylicacid

To a solution of ethyl(1,2-trans)-2-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)-ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)cyclopentane-1-carboxylate(0.20 g, 0.34 mmol) in tetrahydrofuran (10 mL) was added aqueoussolution of lithium hydroxide (0.2 M, 1.02 mmol, 5.10 mL). The reactionmixture was stirred at ambient temperature for 16 h. The reaction waspartially concentrated and diluted with ethyl acetate (50 mL). Thelayers were separated and the aqueous layer was acidified with 1Maqueous hydrochloric acid, and extracted with ethyl acetate (3×25 mL).The combined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by reverse-phase LC to afford the title compound as a colorlesssolid (0.14 g, 71% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 9.77 (s, 1H),7.77 (s, 1H), 7.66 (d, J=1.7 Hz, 2H), 7.29 (d, J=8.5 Hz, 1H), 6.96 (d,J=13.6 Hz, 1H), 4.63-4.50 (m, 1H), 3.99 (d, J=5.5 Hz, 2H), 3.82 (dd,J=7.1, 14.8 Hz, 1H), 3.69 (d, J=11.8 Hz,1H), 3.36 (d, J=10.2 Hz, 1H),3.16 (dd, J=7.8, 15.6 Hz, 1H), 2.84 (s, 2H), 2.18-1.85 (m, 6H),1.85-1.47 (m, 9H), 0.96-0.80 (m, 2H), 0.69-0.53 (m, 2H); MS (ES+) m/z564.1, 562.1 (M+1); (ES−) m/z 562.1, 560.1 (M−1).

Example 10 Synthesis of(1,2-trans)-2-(5-cyclopropyl-4-((3,5-dichlorophenoxy)methyl)-2-fluorobenzoyl)cyclopentane-1-carboxylicacid

Step 1. Preparation of5-cyclopropyl-4-((3,5-dichlorophenoxy)methyl)-2-fluorobenzoyl chloride

To a stirred suspension of5-cyclopropyl-4-((3,5-dichlorophenoxy)methyl)-2-fluorobenzoic acid(prepared accordingly as described in WO2014008458) (0.6 g, 1.72 mmol)in dichloromethane (9 mL) was added oxalyl chloride (0.95 mL, 10.9 mmol)followed by N,N-dimethylformamide (2 drops, catalytic). The suspensionwas stirred for 3 h, resulting in a pale yellow solution. The reactionwas concentrated and the resulting solid (0.66 g, 99%) was used withoutfurther purification: ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J=7.0 Hz, 1H),7.33 (d, J=11.4 Hz, 1H), 7.04 (t, J=1.7 Hz, 1H), 6.90 (d, J=1.7 Hz, 2H),5.25 (s, 2H), 1.91-1.81 (m, 1H), 1.10-1.04 (m, 2H), 0.78-0.73 (m, 2H).

Step 2. Preparation of ethyl(1,2-trans)-2-(5-cyclopropyl-4-((3,5-dichlorophenoxy)methyl)-2-fluorobenzoyl)cyclopentane-1-carboxylate

Following the procedure as described in Example 1 (Step 3) and makingnon-critical variations as required to replace4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl chloride with 5-cyclopropyl-4-((3 ,5 -dichlorophenoxy)methyl)-2-fluorobenzoyl chloride,the title compound was obtained as a colorless gum (0.14 g, 54% yield):MS (ES+) m/z 481.0, 479.0 (M+1).

Step 3. Preparation of(1,2-trans)-2-(5-cyclopropyl-4-((3,5-dichlorophenoxy)methyl)-2-fluorobenzoyl)cyclopentane-1-carboxylicacid

To a solution of ethyl(1,2-trans)-2-(5-cyclopropyl-4-((3,5-dichlorophenoxy)methyl)-2-fluorobenzoyl)cyclopentane-1-carboxylate(0.14 g, 0.30 mmol) in tetrahydrofuran (6 mL) was added aqueous solutionof lithium hydroxide (0.2 M, 0.90 mmol, 4.5 mL). The reaction mixturewas stirred at ambient temperature for 16 h. The reaction was partiallyconcentrated, diluted with water (20 mL) and acidified with 1M aqueoushydrochloric acid, and extracted with ethyl acetate (3 x 35 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue wascrystallized from methanol to afford the title compound as a colorlesssolid (0.076 g, 56% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 12.27 (s, 1H),7.46-7.38 (m, 2H), 7.26 (d, J=1.8 Hz, 2H), 7.22 (t, J=1.7 Hz, 1H), 5.36(s, 2H), 3.92-3.85 (m, 1H), 3.17-3.16 (m, 1H), 2.10-1.90 (m, 3H),1.82-1.57 (m, 4H), 0.99-0.92 (m, 2H), 0.74-0.64 (m, 2H); MS (ES−) m/z449.0, 451.0 (M−1).

Examples 11 and 12 Synthesis of2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methylcyclopentane-1-carboxylic acid

Step 1. Preparation of ethyl 2-iodo-5-methylcyclopentane-1-carboxylate

To a stirred solution of triphenylphosphine (1.89 g, 7.2 mmol), andethyl 2-hydroxy-5-methylcyclopentane-1-carboxylate (0.62 g, 3.69 mmol)in anhydrous tetrahydrofuran (25 mL), iodine (0.74 g, 10.8 mmol) wasadded at 0° C. The reaction mixture was stirred at an ambienttemperature for 16 h, diluted with ethyl acetate (70 mL), and washedwith saturated sodium thiosulfate (70 mL), saturated ammonium chloride(70 mL), brine (50 mL) and dried over sodium sulfate. The solid wasfiltered and solvent was concentrated in vacuo. The residue was purifiedby flash chromatography with gradient 0% to 10% ethyl acetate in hexanesto afford the title compound as a colorless liquid (0.72 g, 69% yield)which was used directly in step 2 without any further characterization:MS (ES+) m/z 283.1 (M+1).

Step 2. Preparation of ethyl2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methylcyclopentane-1-carboxylate

Following the procedure as described in Example 1 (Step 3) and makingnon-critical variations as required to replace ethyl2-iodocyclopentane-1-carboxylate with ethyl2-iodo-5-methylcyclopentane-1-carboxylate, the title compound wasobtained as a colorless gum (0.14 g, 54% yield) which was subjected tonext step without any further characterization: MS (ES+) m/z 483.4(M+1).

Step 3. Preparation of2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methylcyclopentane-1-carboxylicacid

Following the procedure as described in Example 1 (Step 4) and makingnon-critical variations as required to replace ethyl2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylatewith ethyl2-(4adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methylcyclopentane-1-carboxylate,the title compound was obtained as a colorless solid (0.11 g, 46%yield): ¹H NMR (300 MHz, CDCl₃) δ 11.25 (br s, 1H), 7.43 (d, J=8.4 Hz,1H), 6.47 (d, J=13.4 Hz, 1H), 4.01-3.89 (m, 1H), 3.52 (s, 2H), 3.04 (t,J=9.06 Hz, 1H), 2.32-2.08 (m, 2H), 2.06-1.95 (m, 4H), 1.94-1.82 (m, 1H),1.81-1.61 (m, 12H), 1.34-1.19 (m, 2H), 1.16 (d, J=6.5 Hz, 3H), 0.92-0.84(m, 2H), 0.66-0.58 (m, 2H); MS (ES+) m/z 455.3 (M+1).

Example 13 Synthesis of(1R,2R)-2-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylic acid

Step 1. Preparation of ethyl(1R,2R)-2-(5-cyclopropyl-2-fluoro-4-hydroxybenzoyl)-cyclopentane-1-carboxylate

To a solution of trans ethyl2-(4-(benzyloxy)-5-cyclopropyl-2-fluorobenzoyl)-cyclopentane-1-carboxylate(0.12 g, 0.29 mmol) in methanol (2.5 mL) was added palladium on charcoal(0.10 g). The flask was brought under vacuum and backfilled with anatmosphere of hydrogen gas and stirred at room temperature for 1 hour.The reaction mixture was then filtered over Celite and the filter padwas washed with ethyl acetate (75 mL). The solvent was concentrated invacuo to afford the title compound as a yellow solid (0.092 g, 98%yields): ¹H NMR (300 MHz, CDCl₃) δ 7.61 (d, J=8.4 Hz, 1H), 6.58-6.54 (m,2H), 4.08 (q, J=6.9 Hz, 2H), 3.95-3.88 (q, J=7.5 Hz, 1H), 3.41 (q, J=7.5Hz, 1H), 2.19-2.03 (m, 2H), 1.88-1.62 (m, 5H), 1.176 (t, J=7.2 Hz, 3H),0.98-0.92 (m, 2H), 0.65-0.60 (m, 2H); MS (ES−) m/z 319.0 (M−1).

Step 2. Preparation of tent-butyl4-((2-cyclopropyl-4-((1R,2R)-2-(ethoxycarbonyl)-cyclopentane-1-carbonyl)-5-fluorophenoxy)methyl)piperidine-1-carboxylate

To a solution of ethyl2-(5-cyclopropyl-2-fluoro-4-hydroxybenzoyl)cyclopentane-1-carboxylate(0.092 g, 0.29 mmol) in N,N-dimethylformamide (2.9 mL) was added cesiumcarbonate (0.14 g, 0.44 mmol) and tent-butyl4-((tosyloxy)methyl)piperidine-1-carboxylate (0.16 g, 0.44 mmol). Thereaction mixture was stirred at 70° C. for 4 h, cooled to ambienttemperature and diluted with saturated aqueous ammonium chloride andextracted with ethyl acetate (3×75 mL). The combined organic layers werewashed with 5% aqueous lithium chloride, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by flashchromatography with ethyl acetate in hexanes to afford the titlecompound as a colorless solid (0.12 g, 82% yield): ¹H NMR (300 MHz,CDCl₃) δ 7.39 (d, J=8.4 Hz, 1H), 6.48 (d, J=13.2 Hz, 1H), 4.18-4.03 (m,6H), 3.91 (q, J=7.5 Hz, 1H), 3.84 (d, J=6.0 Hz, 2H), 3.39 (q, J=7.8 Hz,1H), 2.78-2.69 (m, 2H), 2.78-2.69 (m, 2H), 2.15-1.95 (m, 4H), 1.87-1.61(m, 6H), 1.44 (s, 9H), 1.16 (t, J=6.3 Hz, 3H), 0.92-0.82 (m, 2H),0.64-0.58 (m, 2H); MS (ES+) m/z 518.3 (M+1).

Step 3. Preparation of ethyl2-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylate

To a solution of tert-butyl4-((2-cyclopropyl-4-2-(ethoxycarbonyl)cyclopentane-1-carbonyl)-5-fluorophenoxy)methyl)piperidine-1-carboxylate(0.12 g, 0.24 mmol) in anhydrous dichloromethane (2.4 mL) was addedtrifluoroacetic acid (0.37 mL, 4.8 mmol). The reaction solution wasstirred for 2 h then concentrated in vacuo. The residue was redissolvedin anhydrous N,N-dimethylformamide (2.4 mL) then cesium carbonate (0.42g, 1.3 mmol) and 2-chloro-5-(trifluoromethyl)benzyl4-methylbenzenesulfonate (0.13 g, 0.45 mmol) were added. The reactionmixture was heated at 80° C. for 16 h. The reaction mixture was cooledto ambient temperature and quenched with saturated sodium bicarbonate(15 mL). The reaction mixture was extracted with ethyl acetate (3×50mL), dried over magnesium sulfate, concentrated in vacuo. The residuewas purified by column chromatography eluting with ethyl acetate inhexanes to afford the title compound as a colorless solid (0.035 g, 24%yield): ¹H NMR (300 MHz, DMSO-d₆) δ 7.79 (br s, 1H), 7.50-7.34 (m, 2H),7.28-7.21 (m, 1H), 6.54-6.47 (m, 1H), 4.079 (m, 2H), 4.00-3.85 (m, 3H),3.64 (br s, 2H), 3.49-3.39 (m, 1H), 2.92 (br s, 2H), 2.26-1.95 (m, 5H),1.88-1.84 (m, 4H), 1.75-1.45 (m, 5H), 1.22-1.14 (m, 3H), 0.95-0.81 (m,2H), 0.71-0.56 (m, 2H); MS (ES+) m/z 612.2, 610.3 (M+1).

Step 4. Preparation oftrans-2-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylicacid

Following the procedure as described in Example 1 (Step 4) and makingnon-critical variations as required to replace ethyl (IR,2R)-2-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylatewith ethyl(1R,2R)-2-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)cyclopentane-1-carboxylate,the title compound was obtained following trituration withdichloromethane as a colorless solid (0.035 g, 99% yield): ¹H NMR (300MHz, DMSO-d₆) δ 12.06 (br s, 1H), 10.57 (br s, 1H), 8.33 (br s, 1H),7.95-7.55 (m, 2H), 7.26 (d, J=8.7 Hz, 1H), 6.93 (d, J=13.8 Hz, 1H), 4.48(br s, 1H), 3.96 (d, J =5.4 Hz, 2H), 3.79 (q, J=7.8 Hz, 1H), 3.58-3.35(m, 1H), 3.12 (q, J=7.8 Hz, 2H), 2.18-1.49 (m, 13H), 0.89-0.83 (m, 2H),0.65-0.51 (m, 2H); MS (ES+) m/z 584.1, 582.2 (M+1).

Example 14 Synthesis of2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)-thio)cyclopentanecarboxylicacid

Step 1. Preparation of1,2-bis(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)disulfane

To a solution of 1-[(4-bromo-2-chloro-5-fluoro-phenoxy)methyl]adamantane(0.40 g, 1.070 mmol) in tetrahydrofuran (2.14 mL, 0.5 M) under nitrogenat 0° C., isopropylmagnesium chloride in tetrahydrofuran (0.59 mL, 1.177mmol, 2 mol/L) was added dropwise . The reaction mixture was allowed towarm to room temperature and ran for 30 minutes. Sulfur (0.172 g, 5.352mmol) was added to the reaction mixture. The reaction was slightlyexothermic and the solution turned a saturated yellow-orange color. Thereaction was ran overnight. Lithium aluminum hydride in tetrahydrofuran(0.67 mL, 1.606 mmol, 2.4 mol/L) was added dropwise to the solution at0° C. The reaction mixture was raised to room temperature and allowed torun for 1.5 hours. The reaction mixture was then quenched with 1M HCl (3mL) followed by sodium bicarbonate (3 mL), and was extracted with EtOAc(3×, 20 mL). The organic layers were collected and combined, dried withMgSO4, and concentrated to give a yellow oil. The material was moved onto the next step as a crude mixture.

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzenethiol

To a solution of1,2-bis(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)di sulfane(0.349 mg, 0.535 mmol) in tetrahydrofuran (1.78 mL, 0.3 M) and ethanol(0.89 mL, 0.6 M), sodium borohydride (0.041 g, 1.070 mmol) was addedportion-wise at 0° C. The reaction mixture was then warmed to roomtemperature and ran for 30 minutes. The reaction was quenched with 1 MHCl to reach pH=7. The crude solution was extracted with EtOAc (3×, 10mL) and the organic layers were collected. The combined organic extractswas washed with water and extracted with 1M KOH (10 mL). The combinedaqueous extracts was extracted once more with EtOAc (10 mL). The organiclayers were combined, dried with MgSO₄, and concentrated to give thedesired thiol as a yellow oil (0.200 g, 57% yield): MS (ES−) m/z: 325(M−1).

Step 3. Preparation of methyl2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)thio)-cyclopentanecarboxylate

To a solution of 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzenethiol(0.10 g, 0.306 mmol) was added to piperidine (0.765 mL, 0.4 M) at roomtemperature, methyl cyclopentene-1-carboxylate (0.116 g, 0.918 mmol) wasadded and the solution was heated to 70° C. The reaction was runovernight. The reaction was cooled to room temperature, quenched with 1MHCl (1 mL), and extracted with EtOAc (3×, 10 mL). The organic layerswere collected and combined, dried with MgSO4, and purified bypreparative TLC in 1% EtOAc/Heptane to give the desired product as amixture of diastereomers (0.035 g, 25% yield): ¹H NMR (400 MHz, CDCl₃) δ7.46 (d, J=7.6 Hz, 1H), 6.65 (dd, J=10.4, 5.2 Hz, 1H), 3.73-3.70 (m,6H), 3.60 (s, 3H), 3.51 (d, J=2.4 Hz, 3H), 2.72 (dt, J=9.0, 6.9 Hz, 1H),2.17-1.99 (m, 8H), 1.92-1.53 (m, 27H); MS(ES+) m/z: 453 (M+1), 475(M+Na).

Step 4. Preparation of2-((4-((3r,5r,7r)-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)thio)-cyclopentanecarboxylicacid

To a solution of2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)thio)-cyclopentanecarboxylate(0.0175 g, 0.0385 mmol) in tetrahydrofuran (0.15 mL, 0.25M) and water(0.15 mL , 0.25M) at 0° C., lithium hydroxide (0.0014 g, 0.057 mmol) wasadded. The reaction was raised to room temperature, then heated to 50°C. and ran overnight. The reaction was cooled to room temperature andconcentrated. The crude mixture was diluted with water and the mixturewas acidified with 1M HCl solution to pH=2. A white solid crashed out ofthe solution. The mixture was diluted with dichloromethane (10 mL) andextracted with dichloromethane (2×, 10 mL). The organic layers werecombined, dried with MgSO_(4,) filtered, concentrated and was purifiedby preparative HPLC to give the desired product as a white solid (0.005g, 27% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (d, J=7.6 Hz, 1H), 7.15(d, J=10.9 Hz, 1H), 3.70 (q, J=6.8 Hz, 1H), 3.64 (s, 2H), 2.59-2.50 (m,1H), 2.08-1.92 (m, 5H), 1.78-1.56 (m, 15H), 1.47 (ddt, J=12.6, 7.4, 6.3Hz, 1H), 1.24 (s, 1H). MS(ES−) m/z: 437 (M−1).

Example 15 Synthesis of +/−trans-2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)-sulfonylcyclopentanecarboxylicacid

Step 1. Preparation of methyl2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)-sulfonylcyclopentanecarboxylate

To a solution of methyl2-(4-(1-adamantylmethoxy)-5-chloro-2-fluoro-phenyl)-sulfanylcyclopentanecarboxylate(100 mg, 0.2208 mmol) in dichloromethane (0.1 M, 2.2 mL) at 0° C.,sodium bicarbonate (0.056 g, 0.6623 mmol, 3 equiv.) was added.3-chloroperoxybenzoic acid (0.148 g, 0.6623 mmol, 3 equiv.) was thenadded portion-wise. The solution first turned a bright orange, then paleyellow color, and slowly a white precipitate was formed. After 3 hours,the crude reaction was diluted with 1N NaOH solution (5 mL) anddichloromethane (5 mL) and was extracted with dichloromethane (3×, 10mL). The organic layers were collected, concentrated, and moved to thenext step as a crude. m/z: 486 (M+1).

Step 2. Preparation of+/−trans-2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)-sulfonylcyclopentanecarboxylicacid

To a the crude methyl2-(4-(1-adamantylmethoxy)-5-chloro-2-fluoro-phenyl)-sulfonyl-cyclopentanecarboxylate(0.1071 mg, 0.2208 mmol) mixture in tetrahydrofuran (1.1 mL, 0.2 M) andwater (1.1 mL, 0.2M) lithium hydroxide (0.053 g, 2.208 mmol, 10 equiv.)was added. The reaction mixture was heated to 50° C. and ran overnight.It was found that in the hydrolysis, all of the sulfone had epimerizedto one isomer, most likely the trans isomer as it is the morethermodynamically favored product. The reaction was then cooled to roomtemperature and acidified to pH=3 with 1M HCl. The crude was dilutedwith water (3 mL) and dichloromethane (3 mL) and was extracted withdichloromethane (3×, 5 mL). The organic layers were collected,concentrated, and purified by preparative HPLC to give a white solid(0.043 g, 41% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (s, 1H), 7.75(d, J=7.2 Hz, 1H), 7.41 (d, J=12.0 Hz, 1H), 4.09 (dt, J=9.0, 6.6 Hz,1H), 3.76 (s, 2H), 2.99 (dt, J=8.9, 6.7 Hz, 1H), 2.12-1.94 (m, 6H),1.81-1.62 (m, 15H); MS (ES+) m/z: 471 (M+1).

Example 16 Synthesis of +/−trans-2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)-sulfinylcyclopentanecarboxylicacid

Step 1. Preparation of methyl2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)-sulfinylcyclopentanecarboxylate

To a solution of methyl2-(4-(1-adamantylmethoxy)-5-chloro-2-fluoro-phenyl)-sulfanylcyclopentanecarboxylate(109 mg, 0.2406 mmol) in dichloromethane (0.1 M, 2.4 mL) at 0° C.,sodium bicarbonate (0.022 g, 0.2647 mmol, 1.1 equiv.) was added.3-chloroperoxybenzoic acid (0.059g, 0.2647 mmol, 1.1 equiv.) was thenadded portion-wise. The solution first turned a bright orange, then paleyellow color, and slowly a white precipitate was formed. After 15minutes, the crude reaction was diluted with 1N NaOH solution (5 mL) anddichloromethane (5 mL) and was extracted with dichloromethane (3x, 10mL). The organic layers were collected, concentrated, and moved to thenext step as a crude. m/z: 470 (M+1).

Step 2. Preparation of+/−trans-2-(S)-(4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)-sulfinylcyclopentanecarboxylicacid and +/−trans-2-(R)-(4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)sulfinylcyclopentanecarboxylic acid

To a the crude methyl2-(4-adamantan-1-ylmethoxy)-5-chloro-2-fluorophenyl)-sulfinylcyclopentanecarboxylate(0.113 g, 0.2405 mmol) mixture in tetrahydrofuran (1.2 mL, 0.2 M) andwater (1.2 mL, 0.2M) lithium hydroxide (0.058 g, 2.405 mmol, 10 equiv.)was added. The reaction mixture was heated to 50° C. and ran overnight.It was found that in the hydrolysis, all of the sulfoxide had epimerizedto one isomer, most likely the trans isomer as it is the morethermodynamically favored product. The reaction was then cooled to roomtemperature and acidified to pH=3 with 1M HCl. The crude was dilutedwith water (3 mL) and dichloromethane (3 mL) and was extracted withdichloromethane (3×, 5 mL). The organic layers were collected,concentrated, and purified by preparative HPLC to give two sulfoxidediastereomers of the desired product as white solids. ¹H NMR (400 MHz,DMSO-d₆) δ 7.48 (d, J=6.9 Hz, 1H), 7.26 (d, J=11.5 Hz, 1H), 3.67 (s,3H), 2.93 (q, J=7.1 Hz, 1H), 2.15 (dq, J=15.5, 7.9, 6.9 Hz, 1H),2.02-1.87 (m, 6H), 1.78-1.54 (m, 16H); ¹H NMR (400 MHz, DMSO-d₆) δ 7.54(d, J=7.0 Hz, 1H), 7.29 (d, J=11.5 Hz, 1H), 3.70 (s, 2H), 3.66-3.55 (m,1H), 2.90 (q, J=7.6 Hz, 1H), 2.03-1.46 (m, 24H); m/z: 455 (M+1).

Example 17 Synthesis of2-((4-adamant-1-ylmethoxy)-5-chloro-2-fluoro-anilino)cyclopentanecarboxylicacid

Step 1. Preparation of ethyl2-((4-adamant-1-ylmethoxy)-5-chloro-2-fluoro-anilino)cyclopentanecarboxylate

In a heat dried microwave vial,1-[(4-bromo-2-chloro-5-fluoro-phenoxy)methyl]adamantane (100 mg, 0.2676mmol), ethyl 2-aminocyclopentanecarboxylate hydrochloride (0.078 g,0.4014 mmol, 1.5 equiv.), cesium carbonate (0.262 g., 0.8028 mmol, 3equiv.) and BrettPhos Pd G1 methyl-t-butyl ether adduct (0.022, 0.02676mmol, 10 mol %) were degassed with nitrogen. Toluene (2.68 mL, 0.1M),which had been degassed, was added. The reaction was refluxed overnight.The crude mixture was cooled to room temperature, diluted with water andisopropyl acetate, and extracted with isopropyl acetate 3× (5 mL). Theorganic layers were collected, combined, and dried with MgSO_(4,) andpurified by column chromatography to give the desired product as amixture of diastereomers, a pale yellow oil in 83% yield. ¹H NMR (400MHz, Chloroform-d) δ 6.96 (s, 1H), 6.88-6.72 (m, 2H), 6.65 (dd, J=12.6,4.7 Hz, 1H), 4.02 (dddd, J=16.3, 11.0, 7.2, 3.9 Hz, 4H), 3.81 (s, 1H),3.56 (s, 2H), 3.43 (s, 2H), 3.06 (q, J=7.3 Hz, 1H), 2.97-2.87 (m, 0H),2.64 (ddd, J=8.8, 7.3, 5.8 Hz, 0H), 2.42 (p, J=6.8 Hz, 1H), 2.26-1.59(m, 29H), 1.54 (s, 3H), 1.39 (d, J=13.2 Hz, 1H), 1.34-1.05 (m, 14H),1.02-0.78 (m, 5H). MS(ES+) m/z: 451 (M+1).

Step 2. Preparation of2-((4-adamant-1-ylmethoxy)-5-chloro-2-fluoroanilino)-cyclopentanecarboxylicacid

To a solution of ethyl2-[4-(1-adamantylmethoxy)-5-chloro-2-fluoro-anilino]-cyclopentanecarboxylate(0.100 g, 0.2222 mmol) in tetrahydrofuran (0.89 mL, 0.25 M) and water(0.89 mL, 0.25 M) at 0° C., lithium hydroxide (0.053 g, 2.22 mmol, 10equiv.) was added. The reaction was raised to room temperature, thenheated to 50° C. and ran overnight. The reaction was cooled to roomtemperature and concentrated. The crude mixture was diluted with waterand the mixture was acidified with 1M HCl solution to pH=2. A whitesolid crashed out of the solution. The mixture was diluted withdichloromethane (5 mL) and extracted with dichloromethane (2×, 5 mL).

The organic layers were combined, dried with MgSO_(4,) filtered,concentrated and was purified by preparative HPLC to give the desireddiastereomer products as white solids (0.0019 g and 0.0022 g, 1.5% and1.76% yield, respectively). NMRs of the compounds were not able to beobtained due to low yields. MS(ES−) m/z: 420 (M−1).

Example 18 Synthesis of2-(4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-methylanilino)-cyclopentanecarboxylicacid

Step 1. Preparation of2-(4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-methylanilino)-cyclopentanecarboxylate

To a solution of ethyl2-(4-(1-adamantylmethoxy)-5-chloro-2-fluoroanilino)-cyclopentanecarboxylate(0.070 g, 0.1556 mmol) in n,n-dimethylformamide (1.56 mL, 0.1 M), sodiumhydride (0.008 g, 0.3111 mmol, 2 equiv.) was added and the solution wasstirred for 30 minutes. Iodomethane (0.096 mL, 1.56 mmol, 10 equiv.) wasthen added dropwise and the solution was stirred for 2 days at roomtemperature. About 50% conversion to the desired product was seen andpresence of dimethylated product was also seen. The reaction wasquenched with 1M HCl (5 mL) and extracted 3× with DCM (5 mL). Theorganic layers were collected, combined, and concentrated. The crudemixture was carried on to the next step as a crude. MS(ES+) m/z: 464(M).

Step 2. Preparation of2-(4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-methylanilino)-cyclopentanecarboxylicacid

To a solution of ethyl 2-[4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-methylanilino]-cyclopentanecarboxylate (0.072 g,0.156 mmol) in tetrahydrofuran (0.62 mL, 0.25 M) and water (0.62 mL,0.25 M) at 0° C., lithium hydroxide (0.037g, 1.56 mmol, 10 equiv.) wasadded. The reaction was raised to room temperature, then heated to 50°C. and ran overnight. The reaction was cooled to room temperature andconcentrated. The crude mixture was diluted with water and the mixturewas acidified with 1M HCl solution to pH=2. A white solid crashed out ofthe solution. There was only one stereoisomer seen on the LC-MS, it washypothesized that the stereochemistry epimerized to trans, thethermodynamically favored product during the hydrolysis. The mixture wasdiluted with dichloromethane (5 mL) and extracted with dichloromethane(2×, 5 mL). The organic layers were combined, dried with MgSO4,filtered, concentrated and was purified by preparative HPLC to give thedesired product, with hypothesized trans stereochemistry, as a whitesolid (0.0039 g, 5.63% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 7.12 (d,J=8.8 Hz, 1H), 6.98 (d, J=13.7 Hz, 1H), 3.91 (q, J=7.3 Hz, 1H), 3.54 (s,2H), 2.62 (s, 3H), 1.98 (s, 4H), 1.81-1.53 (m, 21H). MS(ES−) m/z: 435(M−1).

Example 19 Tritiated Compound Binding to membranes isolated from cellsthat heterologously express hNav1.7 and the β1 subunit

Preparation of membranes containing recombinantly expressed sodiumchannels: Frozen recombinant cell pellets were thawed on ice and dilutedto 4 times the cell pellet weight with ice cold 50 mM Tris HCl, pH 7.4buffer. The cell suspensions were homogenized on ice using a motorizedglass dounce homogeniser. Homogenates were further diluted 8.4 timeswith ice cold 50 mM Tris HC1, pH 7.4 buffer and then centrifuged at 200×g at 4° C. for 15 min. The supernatants were collected and centrifugedat 10000× g at 4° C. for 50 min. The pellets were then re-suspended in100 mM NaCl, 20 mM Tris HCl , pH 7.4 buffer containing 1% v/v proteaseinhibitors

(Calbiochem) and re-homogenized on ice. The homogenized membranes werethen processed through a syringe equipped with a 26 gauge needle.Protein concentrations were determined by Bradford Assay and themembranes were stored at −80° C.

Radioligand Binding Studies: Saturation experiments. A competitiveNaV1.7 inhibitor having a methyl group was tritiated. Three tritiumswere incorporated in place of methyl hydrogens to generate [³H]compound.Binding of this radioligand was performed in 5 mL borosilicate glasstest tubes at room temperature. Binding was initiated by addingmembranes to increasing concentrations of [³H]compound in 100 mM NaCl,20 mM Tris HCl, pH 7.4 buffer containing 0.01% w/v bovine serum albumin(BSA) for 18h. Non-specific binding was determined in the presence of 1μM unlabeled compound. After 18h, the reactants were filtered throughGF/C glass fiber filters presoaked in 0.5% w/v polyethylene imine.Filters were washed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl,pH7.4 buffer containing 0.25% BSA to separate bound from free ligand.[³H]compound bound to filters was quantified by liquid scintillationcounting.

Competitive binding experiments: Binding reactions were performed in96-well polypropylene plates at room temperature for 18h. In 360 μL,membranes were incubated with 100 pM [³H]compound and increasingconcentrations of Test Compound. Non-specific binding was defined in thepresence of 1 μM unlabeled compound. Reactions were transferred andfiltered through 96-well glass fiber/C filter plates presoaked with 0.5%polyethylene imine. The filtered reactions were washed 5 times with 200μL ice cold buffer containing 0.25% BSA. Bound radioactivity wasdetermined by liquid scintillation counting.

Data Analysis: For saturation experiments, non-specific binding wassubtracted from total binding to provide specific binding and thesevalues were recalculated in terms of pmol ligand bound per mg protein.Saturation curves were constructed and dissociation constants werecalculated using the single site ligand binding model:Beq=(Bmax*X)/(X+Kd), where Beq is the amount of ligand bound atequilibrium, Bmax is the maximum receptor density, Kd is thedissociation constant for the ligand, and X is the free ligandconcentration. For competition studies percent inhibition was determinedand IC₅₀ values were calculated using a 4 parameter logistic model (%inhibition=(A+((B−A)/(1+((x/C)̂D)))) using XLfit, where A and B are themaximal and minimum inhibition respectively, C is the IC₅₀ concentrationand D is the (Hill) slope.

Representative compounds, when tested in this model, demonstratedaffinities as set forth in Table 1.

TABLE 1 Na_(V)1.7 (LBA) Example Structure (μM) 1

0.009 2

0.51 3

4.2 4

0.44 5

3.1 6

0.055 7

0.76 8

0.86 9

0.051 10

0.021 11

0.7 12

0.003 13

0.021 14

2.63 15

0.454 16

1.29 17

3.02 18

>10

Example 19 Analgesia Induced by Sodium Channel Blockers Heat InducedTail Flick Latency Test

In this test, the analgesia effect produced by administering a compoundof the invention can be observed through heat-induced tail-flick inmice. The test includes a heat source consisting of a projector lampwith a light beam focused and directed to a point on the tail of a mousebeing tested. The tail-flick latencies, which are assessed prior to drugtreatment, and in response to a noxious heat stimulus, i.e., theresponse time from applying radiant heat on the dorsal surface of thetail to the occurrence of tail flick, are measured and recorded at 40,80, 120, and 160 minutes.

For the first part of this study, 65 animals undergo assessment ofbaseline tail flick latency once a day over two consecutive days. Theseanimals are then randomly assigned to one of the 11 different treatmentgroups including a vehicle control, a morphine control, and 9 compoundsat 30 mg/Kg are administered intramuscularly. Following doseadministration, the animals are closely monitored for signs of toxicityincluding tremor or seizure, hyperactivity, shallow, rapid or depressedbreathing and failure to groom. The optimal incubation time for eachcompound is determined via regression analysis. The analgesic activityof the test compounds is expressed as a percentage of the maximumpossible effect (%MPE) and is calculated using the following formula:

$\% \mspace{14mu} {MPE}\mspace{20mu} \frac{{{Postdrug}\mspace{14mu} {latency}} - {{Predrug}\mspace{14mu} {latency}}}{{{Cut}\text{-}{off}\mspace{14mu} {time}\mspace{14mu} ( {10\mspace{14mu} s} )} - {{Predrug}\mspace{14mu} {latency}}} \times 100\%$

where:

Postdrug latency=the latency time for each individual animal takenbefore the tail is removed (flicked) from the heat source afterreceiving drug.

Predrug latency=the latency time for each individual animal taken beforethe tail is flicked from the heat source prior to receiving drug.

Cut-off time (10 s)=is the maximum exposure to the heat source.

Acute Pain (Formalin Test)

The formalin test is used as an animal model of acute pain. In theformalin test, animals are briefly habituated to the plexiglass testchamber on the day prior to experimental day for 20 minutes. On the testday, animals are randomly injected with the test articles. At 30 minutesafter drug administration, 50 μL of 10% formalin is injectedsubcutaneously into the plantar surface of the left hind paw of therats. Video data acquisition begins immediately after formalinadministration, for duration of 90 minutes.

The images are captured using the Actimetrix Limelight software whichstores files under the *.11ii extension, and then converts it into theMPEG-4 coding. The videos are then analyzed using behaviour analysissoftware “The Observer 5.1”, (Version 5.0, Noldus InformationTechnology, Wageningen, The Netherlands). The video analysis isconducted by watching the animal behaviour and scoring each according totype, and defining the length of the behaviour (Dubuisson and Dennis,1977). Scored behaviours include: (1) normal behaviour, (2) putting noweight on the paw, (3) raising the paw, (4) licking/biting or scratchingthe paw. Elevation, favoring, or excessive licking, biting andscratching of the injected paw indicate a pain response. Analgesicresponse or protection from compounds is indicated if both paws areresting on the floor with no obvious favoring, excessive licking, bitingor scratching of the injected paw.

Analysis of the formalin test data is done according to two factors: (1)Percent Maximal Potential Inhibitory Effect (%MPIE) and (2) pain score.The %MPIEs is calculated by a series of steps, where the first is to sumthe length of non-normal behaviours (behaviours 1,2,3) of each animal. Asingle value for the vehicle group is obtained by averaging all scoreswithin the vehicle treatment group. The following calculation yields theMPIE value for each animal:

MPIE (%) =100−[(treatment sum/average vehicle value)×100% ]

The pain score is calculated from a weighted scale as described above.The duration of the behaviour is multiplied by the weight (rating of theseverity of the response), and divided by the total length ofobservation to determine a pain rating for each animal. The calculationis represented by the following formula:

Pain rating=[0(T0)+1(T1)+2(T2)+3(T3)]/(T0+T1 +T2+T3)

CFA Induced Chronic Inflammatory Pain

In this test, tactile allodynia is assessed with calibrated von Freyfilaments. Following a full week of acclimatization to the vivariumfacility, 150 μL of the “Complete Freund's Adjuvant” (CFA) emulsion (CFAsuspended in an oil/saline (1:1) emulsion at a concentration of 0.5mg/mL) is injected subcutaneously into the plantar surface of the lefthind paw of rats under light isoflurane anaesthesia. Animals are allowedto recover from the anaesthesia and the baseline thermal and mechanicalnociceptive thresholds of all animals are assessed one week after theadministration of CFA. All animals are habituated to the experimentalequipment for 20 minutes on the day prior to the start of theexperiment. The test and control articles are administrated to theanimals, and the nociceptive thresholds measured at defined time pointsafter drug administration to determine the analgesic responses to eachof the six available treatments. The time points used are previouslydetermined to show the highest analgesic effect for each test compound.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Animals are placed in a Plexiglas enclosure set on topof an elevated glass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 30° C. forall test trials. Animals are allowed to accommodate for 20 minutesfollowing placement into the enclosure until all exploration behaviourceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter (IITC,Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 45 respectively, and a cut off time of 20seconds is employed to prevent tissue damage.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.) following the Hargreaves test. Animals areplaced in an elevated Plexiglas enclosure set on a mire mesh surface.After 10 minutes of accommodation, pre-calibrated Von Frey hairs areapplied perpendicularly to the plantar surface of both paws of theanimals in an ascending order starting from the 0.1 g hair, withsufficient force to cause slight buckling of the hair against the paw.Testing continues until the hair with the lowest force to induce a rapidflicking of the paw is determined or when the cut off force ofapproximately 20 g is reached. This cut off force is used because itrepresent approximately 10% of the animals' body weight and it serves toprevent raising of the entire limb due to the use of stiffer hairs,which would change the nature of the stimulus.

Postoperative Models of Nociception

In this model, the hypealgesia caused by an intra-planar incision in thepaw is measured by applying increased tactile stimuli to the paw untilthe animal withdraws its paw from the applied stimuli. While animals areanaesthetized under 3.5% isofluorane, which is delivered via a nosecone, a 1 cm longitudinal incision is made using a number 10 scalpelblade in the plantar aspect of the left hind paw through the skin andfascia, starting 0.5 cm from the proximal edge of the heel and extendingtowards the toes. Following the incision, the skin is apposed using 2,3-0 sterilized silk sutures. The injured site is covered with Polysporinand Betadine. Animals are returned to their home cage for overnightrecovery.

The withdrawal thresholds of animals to tactile stimuli for bothoperated (ipsilateral) and unoperated (contralateral) paws can bemeasured using the Model 2290 Electrovonfrey anesthesiometer (IITC LifeScience, Woodland Hills, Calif.). Animals are placed in an elevatedPlexiglas enclosure set on a mire mesh surface. After at least 10minutes of acclimatization, pre-calibrated Von Frey hairs are appliedperpendicularly to the plantar surface of both paws of the animals in anascending order starting from the 10 g hair, with sufficient force tocause slight buckling of the hair against the paw. Testing continuesuntil the hair with the lowest force to induce a rapid flicking of thepaw is determined or when the cut off force of approximately 20 g isreached. This cut off force is used because it represent approximately10% of the animals' body weight and it serves to prevent raising of theentire limb due to the use of stiffer hairs, which would change thenature of the stimulus.

Neuropathic pain model; Chronic Constriction Injury

Briefly, an approximately 3 cm incision is made through the skin and thefascia at the mid thigh level of the animals' left hind leg using a no.10 scalpel blade. The left sciatic nerve is exposed via blunt dissectionthrough the biceps femoris with care to minimize haemorrhagia. Fourloose ligatures are tied along the sciatic nerve using 4-0non-degradable sterilized silk sutures at intervals of 1 to 2 mm apart.The tension of the loose ligatures is tight enough to induce slightconstriction of the sciatic nerve when viewed under a dissectionmicroscope at a magnification of 4 fold. In the sham-operated animal,the left sciatic nerve is exposed without further manipulation.Antibacterial ointment is applied directly into the wound, and themuscle is closed using sterilized sutures. Betadine is applied onto themuscle and its surroundings, followed by skin closure with surgicalclips.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals are placed in an elevated Plexiglasenclosure set on a mire mesh surface. After 10 minutes of accommodation,pre-calibrated Von Frey hairs are applied perpendicularly to the plantarsurface of both paws of the animals in an ascending order starting fromthe 0.1 g hair, with sufficient force to cause slight buckling of thehair against the paw. Testing continues until the hair with the lowestforce to induce a rapid flicking of the paw is determined or when thecut off force of approximately 20 g is reached. This cut off force isused because it represents approximately 10% of the animals' body weightand it serves to prevent raising of the entire limb due to the use ofstiffer hairs, which would change the nature of the stimulus.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Following the measurement of tactile thresholds,animals are placed in a Plexiglass enclosure set on top of an elevatedglass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 24 to 26oC for all test trials. Animals are allowed to accommodate for 10minutes following placement into the enclosure until all explorationbehaviour ceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter(IITC, Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 55 respectively, and a cut off time of 20seconds is used to prevent tissue damage.

Neuropathic pain model: Spinal Nerve Ligation

The spinal nerve ligation (SNL) neuropathic pain model is used as ananimal (i.e. rat) model of neuropathic pain. In the SNL test, the lumbarroots of spinal nerves L5 and L6 are tightly ligated to cause nerveinjury, which results in the development of mechanical hyperalgesia,mechanical allodynia and thermal hypersensitivity. The surgery isperformed two weeks before the test day in order for the pain state tofully develop in the animals. Several spinal nerve ligation variationsare used to characterize the analgesic properties of a compound of theinvention.

Ligation of the L5 spinal nerve;

Ligation of the L5 and L6 spinal nerves;

Ligation and transection of the L5 spinal nerve;

Ligation and transection of the L5 and L6 spinal nerves; or

Mild irritation of the L4 spinal nerve in combination with any one ofthe above (1)-(4).

While the animals are anaesthetized under 3.5% isofluorane delivered viaa nose cone, an approximately 2.5 cm longitudinal incision is made usinga number 10 scalpel blade in the skin just lateral to the dorsalmidline, using the level of the posterior iliac crests as the midpointof the incision. Following the incision, the isoflourane is readjustedto maintenance levels (1.5%-2.5%). At mid-sacral region, an incision ismade with the scalpel blade, sliding the blade along the side of thevertebral column (in the saggital plane) until the blade hits thesacrum. Scissors tips are introduced through the incision and the muscleand ligaments are removed from the spine to expose 2-3 cm of thevertebral column. The muscle and fascia are cleared from the spinalvertebra in order to locate the point where the nerve exits from thevertebra. A small glass hook is placed medial to the spinal nerves andthe spinal nerves are gently elevated from the surrounding tissues. Oncethe spinal nerves have been isolated, a small length of non-degradable6-0 sterilized silk thread is wound twice around the ball at the tip ofthe glass hook and passed back under the nerve. The spinal nerves arethen firmly ligated by tying a knot, ensuring that the nerve bulges onboth sides of the ligature. The procedure may be repeated as needed. Insome animals, the L4 spinal nerve may be lightly rubbed (up to 20 times)with the small glass hook to maximize the development of neuropathicpain. Antibacterial ointment is applied directly into the incision, andthe muscle is closed using sterilized sutures. Betadine is applied ontothe muscle and its surroundings, followed by skin closure with surgicalstaples or sterile non-absorable monofilament 5-0 nylon sutures.

The analgesic effect produced by topical administration of a compound ofthe invention to the animals can then be observed by measuring the pawwithdrawal threshold of animals to mechanical tactile stimuli. These maybe measured using either the mechanical allodynia procedure or themechanical hyperalgesia procedure as described below. Afterestablishment of the appropriate baseline measurements by either method,topical formulation of a compound of the invention is applied on theipsilateral ankle and foot. The animals are then placed in plastictunnels for 15 minutes to prevent them from licking the treated area andremoving the compound. Animals are placed in the acrylic enclosure for15 minutes before testing the ipsilateral paw by either of the methodsdescribed below, and the responses are recorded at 0.5, 1.0 and 2.0 hourpost treatment. Mechanical allodynia method

The pain threshold of animals to mechanical alloydnia for both operatedand control animals can be measured approximately 14 days post-surgeryusing manual calibrated von Frey filaments as follows. Animals areplaced in an elevated plexiglass enclosure set on a mire mesh surface.Animals are allowed to acclimate for 20-30 minutes. Pre-calibrated VonFrey hairs are applied perpendicularly to the plantar surface of theipsilateral paw of the animals starting from the 2.0 g hair, withsufficient force to cause slight buckling of the hair against the paw toestablish the baseline measurements. Stimuli are presented in aconsecutive manner, either in an ascending or descending order until thefirst change in response is noted, after which four additional responsesare recorded for a total of six responses. The six responses measured ingrams are entered into a formula as described by Chaplan, S. R. et al.,J. Neurosci. Methods, 1994 Jul;53(1):55-63, and a 50% withdrawalthreshold is calculated. This constitutes the mechanical allodyniavalue.

Mechanical hyperalgesia method

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals are placed in an elevated Plexiglasenclosure set on a wire mesh surface. After 15 minutes of accommodationin this enclosure, a von Frey hair is applied perpendicularly to theplantar surface of the ipsilateral hind paws of the animals, withsufficient force, measured in grams, to elicit a crisp response of thepaw. A response indicates a withdrawal from the painful stimulus andconstitutes the efficacy endpoint. The data are expressed as percentchange from baseline threshold measured in grams.

Example 20 In Vivo Assay for Treatment of Pruritis

The compounds of the invention can be evaluated for their activity asantipruritic agents by in vivo test using rodent models. One establishedmodel for peripherally elicited pruritus is through the injection ofserotonin into the rostral back area (neck) in hairless rats. Prior toserotonin injections (e.g., 2 mg/mL, 50 μL), a dose of a compound of thepresent invention can be applied systemically through oral, intravenousor intraperitoneal routes or topically to a circular area fixed diameter(e.g. 18 mm). Following dosing, the serotonin injections are given inthe area of the topical dosing. After serotonin injection the animalbehaviour is monitored by video recording for 20 min-1.5 h, and thenumber of scratches in this time compared to vehicle treated animals.Thus, application of a compound of the current invention could suppressserotonin-induced scratching in rats.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

We claim:
 1. A compound of Formula I:

or a salt thereof; wherein each RAA is independently selected from thegroup consisting of F, Cl, Br, I, —CN, —OR^(A1), —(X^(RA))-(6-12membered aryl), —(X^(RA))-(5-12 membered heteroaryl), and —R^(A2),wherein said 6-12 membered aryl and 5-12 membered heteroaryl of R^(AA)is optionally substituted with from 1 to 5 substitutents independentlyselectd from the group consisting of F, Cl, Br, I, C₁₋₄ alkyl, C₁₋₄haloalkyl, and C₁₋₄(halo)alkoxy; R^(A1) is selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈cycloalkyl, phenyl and benzyl; RA^(A2) is selected from the groupconsisting of C₁₋₈ alkyl that is optionally substituted with one or moresubstituents selected from oxo (=O), fluoro, amino, C₁₋₄ alkylamino anddi(C₁₋₄alkyl)amino; X^(RA) is selected from the group consisting ofabsent, —C(=O)—, and C₁₋₄ alkylene; wherein any C₁₋₄ alkylene of X^(RA)is optionally substituted with 1 to 3 substituents selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, and phenyl that isoptionally substituted with 1 to 5 substitutents selected from, F, Cl,Br, I, —NH_(2,) —OH, —CN, —NO_(2,) C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄(halo)alkoxy, C₁₋₄ alkylamino and C₁₋₄ dialkylamino; n is 0,1, 2, 3, 4, 5, 6, 7, or 8; ring “A” is a 3-15 membered carbocyclyl, a6-12 membered aryl, a 5-12 membered heteroaryl, or a 3-15 memberedheterocyclyl; X¹ and X² are each independently selected from the groupconsisting of absent, —S—, —O— and —N(R^(X))— wherein R^(x) is H, C₁₋₈alkyl, or C₁₋₈ haloalkyl, and wherein if the subscript m is 0 then oneof X¹ or X² is absent; L is C₁₋₆ alkylene, wherein L is optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halo, oxo (=O), andC₁₋₄ haloalkyl; wherein any two substituents attached to the same atomon L are optionally combined to form a 3-to 5- membered carbocyclicring; m is 0 or 1; R², R³, R⁴, and R⁵ are each independently selectedfrom the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₃₋₈cycloalkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy; X is selected from the groupconsisting of O, S, S=O, SO_(2,) N(R^(N)), C=O, CH_(2,) and C=S, whereinR^(N) is selected from the group consisting of H, C₁₋₆ alkyl and acyl;ring “B” is selected from the group consisting of cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, wherein ring B isoptionally substituted with one or more groups independently selectedfrom C₁₋₄ alkyl; and R⁶ is hydrogen or C₁₋₆ alkyl.